HCSGD entry for CDKN2A

1. General information

Official gene symbol	CDKN2A
Entrez ID	1029
Gene full name	cyclin-dependent kinase inhibitor 2A
Other gene symbols	ARF CDK4I CDKN2 CMM2 INK4 INK4A MLM MTS-1 MTS1 P14 P14ARF P16 P16-INK4A P16INK4 P16INK4A P19 P19ARF TP16
Links to Entrez Gene	Links to Entrez Gene

2. Neighbors in the network

3. Gene ontology annotation

GO ID	GO term	Evidence	Category
GO:0000075	Cell cycle checkpoint	IMP	biological_process
GO:0000082	G1/S transition of mitotic cell cycle	IDA	biological_process
GO:0000209	Protein polyubiquitination	IDA	biological_process
GO:0000278	Mitotic cell cycle	TAS	biological_process
GO:0001953	Negative regulation of cell-matrix adhesion	IMP	biological_process
GO:0002039	P53 binding	IPI	molecular_function
GO:0003677	DNA binding	IEA	molecular_function
GO:0004861	Cyclin-dependent protein serine/threonine kinase inhibitor activity	IDA	molecular_function
GO:0005515	Protein binding	IPI	molecular_function
GO:0005634	Nucleus	IDA	cellular_component
GO:0005654	Nucleoplasm	IDA	cellular_component
GO:0005730	Nucleolus	IDA	cellular_component
GO:0005737	Cytoplasm	IDA	cellular_component
GO:0005739	Mitochondrion	IEA	cellular_component
GO:0005829	Cytosol	TAS	cellular_component
GO:0006351	Transcription, DNA-templated	IEA	biological_process
GO:0006364	RRNA processing	IEA	biological_process
GO:0006469	Negative regulation of protein kinase activity	IMP	biological_process
GO:0006919	Activation of cysteine-type endopeptidase activity involved in apoptotic process	IMP	biological_process
GO:0007050	Cell cycle arrest	IDA IMP	biological_process
GO:0007265	Ras protein signal transduction	IEP	biological_process
GO:0008134	Transcription factor binding	IPI	molecular_function
GO:0008285	Negative regulation of cell proliferation	IDA IMP	biological_process
GO:0008637	Apoptotic mitochondrial changes	IMP	biological_process
GO:0010389	Regulation of G2/M transition of mitotic cell cycle	IMP	biological_process
GO:0016301	Kinase activity	IEA	molecular_function
GO:0016604	Nuclear body	IDA	cellular_component
GO:0019901	Protein kinase binding	IPI	molecular_function
GO:0030308	Negative regulation of cell growth	IDA	biological_process
GO:0030889	Negative regulation of B cell proliferation	ISS	biological_process
GO:0031647	Regulation of protein stability	ISS	biological_process
GO:0031648	Protein destabilization	IDA	biological_process
GO:0032088	Negative regulation of NF-kappaB transcription factor activity	IDA	biological_process
GO:0033088	Negative regulation of immature T cell proliferation in thymus	ISS	biological_process
GO:0033235	Positive regulation of protein sumoylation	IMP	biological_process
GO:0034393	Positive regulation of smooth muscle cell apoptotic process	ISS	biological_process
GO:0035985	Senescence-associated heterochromatin focus	IDA	cellular_component
GO:0035986	Senescence-associated heterochromatin focus assembly	IMP	biological_process
GO:0042326	Negative regulation of phosphorylation	IDA	biological_process
GO:0043234	Protein complex	IDA	cellular_component
GO:0043517	Positive regulation of DNA damage response, signal transduction by p53 class mediator	IDA	biological_process
GO:0045736	Negative regulation of cyclin-dependent protein serine/threonine kinase activity	IDA	biological_process
GO:0045892	Negative regulation of transcription, DNA-templated	IMP	biological_process
GO:0045893	Positive regulation of transcription, DNA-templated	IDA	biological_process
GO:0045944	Positive regulation of transcription from RNA polymerase II promoter	IDA	biological_process
GO:0046825	Regulation of protein export from nucleus	IMP	biological_process
GO:0048103	Somatic stem cell division	ISS	biological_process
GO:0050821	Protein stabilization	IDA	biological_process
GO:0051059	NF-kappaB binding	IDA	molecular_function
GO:0051444	Negative regulation of ubiquitin-protein ligase activity	ISS	biological_process
GO:0055105	Ubiquitin-protein ligase inhibitor activity	ISS	molecular_function
GO:0070534	Protein K63-linked ubiquitination	IDA	biological_process
GO:0071158	Positive regulation of cell cycle arrest	IDA	biological_process
GO:0090398	Cellular senescence	IMP	biological_process
GO:0090399	Replicative senescence	IMP	biological_process
GO:0097371	MDM2/MDM4 family protein binding	IPI	molecular_function
GO:1902510	Regulation of apoptotic DNA fragmentation	IMP	biological_process
GO:2000111	Positive regulation of macrophage apoptotic process	ISS	biological_process
GO:2000774	Positive regulation of cellular senescence	IMP	biological_process

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4. Expression levels in datasets

Meta-analysis result

p-value up	p-value down	FDR up	FDR down
0.0002636792	0.9984346833	0.0447761290	1.0000000000

Individual experiment result
( "-" represent NA in the specific microarray platform )

Data source	Up or down	Log fold change
GSE11954	Up	0.4502731436
GSE13712_SHEAR	Up	1.9587716370
GSE13712_STATIC	Up	1.3699114008
GSE19018	Up	0.4272625384
GSE19899_A1	Up	0.6279932626
GSE19899_A2	Up	1.0876646741
PubMed_21979375_A1	Up	1.7189900734
PubMed_21979375_A2	Up	1.3021958095
GSE35957	Up	0.8006880685
GSE36640	Up	1.3495616663
GSE54402	Up	0.5576839018
GSE9593	Up	1.1048462620
GSE43922	Up	0.4102884239
GSE24585	Down	-0.1020499608
GSE37065	Up	0.4231093992
GSE28863_A1	Down	-0.0871235379
GSE28863_A2	Down	-0.0496995647
GSE28863_A3	Up	0.1072384030
GSE28863_A4	Up	0.1181997650
GSE48662	Up	0.2677757340

5. Regulation relationships with compounds/drugs/microRNAs

Compounds

Not regulated by compounds

Drugs

Not regulated by drugs

MicroRNAs

mirTarBase

MiRNA_name	mirBase ID	miRTarBase ID	Experiment	Support type	References (Pubmed ID)
hsa-miR-10b-5p	MIMAT0000254	MIRT006368	Luciferase reporter assay//Western blot	Functional MTI	21471404
hsa-miR-10b-5p	MIMAT0000254	MIRT006368	CLASH	Functional MTI (Weak)	23622248
hsa-miR-24-3p	MIMAT0000080	MIRT004362	qRT-PCR//Western blot//Reporter assay;Other	Functional MTI	18365017
hsa-let-7g-5p	MIMAT0000414	MIRT004489	qRT-PCR//Luciferase reporter assay//Western blot//Western blot;qRT-PCR;Proteomics;Other	Functional MTI	20309945
hsa-miR-125b-5p	MIMAT0000423	MIRT004709	Western blot	Functional MTI	20347935
hsa-miR-155-5p	MIMAT0000646	MIRT020886	Proteomics	Functional MTI (Weak)	18668040
hsa-miR-124-3p	MIMAT0000422	MIRT022931	Proteomics;Microarray	Functional MTI (Weak)	18668037
hsa-miR-215-5p	MIMAT0000272	MIRT024932	Microarray	Functional MTI (Weak)	19074876
hsa-miR-34a-5p	MIMAT0000255	MIRT025556	Western blot	Non-Functional MTI	21128241
hsa-miR-192-5p	MIMAT0000222	MIRT026702	Microarray	Functional MTI (Weak)	19074876
hsa-miR-16-5p	MIMAT0000069	MIRT031803	Proteomics	Functional MTI (Weak)	18668040
hsa-miR-455-3p	MIMAT0004784	MIRT037910	CLASH	Functional MTI (Weak)	23622248
hsa-miR-423-5p	MIMAT0004748	MIRT038036	CLASH	Functional MTI (Weak)	23622248
hsa-miR-296-3p	MIMAT0004679	MIRT038476	CLASH	Functional MTI (Weak)	23622248
hsa-miR-615-3p	MIMAT0003283	MIRT039976	CLASH	Functional MTI (Weak)	23622248
hsa-miR-320a	MIMAT0000510	MIRT044426	CLASH	Functional MTI (Weak)	23622248

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mirRecord

MicroRNA name	mirBase ID	Target site number	MiRNA mature ID	Test method inter	MiRNA regulation site	Pubmed ID
hsa-miR-24-3p	MIMAT0000080	2	hsa-miR-24	{Western blot}{Western blot}	{overexpression by miRNA precursor transfection}{underexpression by 2'-O-Me antisense miRNA oligonucleotides}	18365017
hsa-miR-24-3p	MIMAT0000080	1	hsa-miR-24	{Western blot}{Western blot}	{overexpression by miRNA precursor transfection}{underexpression by 2'-O-Me antisense miRNA oligonucleotides}	18365017
hsa-miR-125b-5p	MIMAT0000423	1	hsa-miR-125b	{Western blot}	{downregulation by anti-miRNA oligonucleotide}	20347935

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6. Text-mining results about the gene

Gene occurances in abstracts of cellular senescence-associated articles: 704 abstracts the gene occurs.

PubMed ID of the article	Sentenece the gene occurs
28123872	This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8+ T cells mediated through downregulation of P21WAF1, P16INK4a, and P53 expression
28036343	Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection
28036343	This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations
28036343	METHODS: Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations
28036343	Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures
28036343	There were no significant associations between p16INK4a expression and cytokines
28036343	CONCLUSIONS: In this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations
28036343	While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants
27861555	In order to investigate the immunological aging in HIV patients, p16 protein expression was evaluated by flow cytometry, in T cell subsets in a cohort of chronically HIV-infected patients on and off ART as well as age-matched healthy controls
27861555	Results showed that untreated HIV-infected subjects exhibited increased per-cell p16 protein expression that was discordant with chronological aging
27861555	ART restored p16 protein expression to levels comparable with HIV-negative subjects in the CD4 compartment, but not in CD8 T cells, which can be an indicative of an irreversible activation/exhaustion status on these cells
27861555	Additionally, the frequency of activated CD4+ and CD8+ T cells was positively correlated with p16 expression in CD4+ and CD8+ T cells in untreated subjects
27861555	Taken together, these data demonstrate that chronic HIV infection is associated with elevated expression of the cellular aging marker p16 in T cells
27861555	ART restored normal p16 levels in the CD4+ T cell compartment, indicating that use of therapy can be of fundamental importance to normal cell cycling and maintaining immune homeostasis
27824900	In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners
27803714	Within passages 4 and 8, senescent cultures exhibited typical morphological features, senescence-associated beta-galactosidase activity, increased levels of p16, and decreased levels of miR-17 and miR-21 but showed differential expression of p21, p53, and ATM dependently on the onset of cell senescence
27547293	Simultaneously, livers from Gunn rats showed decreased expression of senescence markers and cell cycle inhibitors p21 and p16
27362652	Senescence markers including p16, p21, p53, and senescence-associated beta-galactosidase (SA-betagal) activity were measured in type II AECs from IPF lungs and unused donor lungs
27362652	Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs
27349711	Compared with the healthy group, hemodialyzed and transplanted patients exhibited a significant decrease in telomere length, an increase in p16(INK4A) mRNA expression and in lymphocytes with 53BP1 foci
27349269	Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a
27349269	In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC
27349269	Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression
27349269	All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a, possibly via the AKT pathway
27349269	Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression
27333655	Overexpression of p16(INK4a) in Mastocytosis (Urticarial Pigmentosa)
27333655	The expression of p16(INK4a) has been reported to induce cell-cycle arrest and cellular senescence
27333655	The p16(INK4a) expression has never been examined in human mast cells and mastocytosis
27333655	We immunohistologically examined the expression of p16(INK4a) and tryptase in 5 normal human skin and 4 mastocytosis
27333655	4 (mean +/- standard deviation) % of tryptase-positive mast cells coexpressed p16(INK4a)
27333655	1%) of tryptase-positive tumor cells was immunoreactive to p16(INK4a) in all of 4 mastocytosis
27333655	The p16(INK4a) overexpression may induce the senescence of neoplastic mast cells to undergo spontaneous regression of mastocytosis
27305909	Further analyses suggest that KD of ING1b results in induction of both cellular senescence and the cell cycle inhibitor p16 INK4a
27305909	The data further suggest that ING2 upregulates p16 INK4a , which is a novel target for ING2
27294914	X), 8-OHdG, p16(Ink4a), Rb, p21(Cip1/Waf1) and p53 in senescent Sca-1(+) HSC/HPCs
27228653	The most studied target genes of Bmi1 are the genes of Ink4 locus, CdkI p16(Ink4a) and p1(Arf), suppression of which due to activating mutations of the BMI1 results in formation of cancer stem cells (CSC) and carcinomas in various tissues
27212655	Senescent cells were identified based on declining population doublings, increased expression of senescence markers p16 and p53 and increased senescence-associated beta-gal activity
27126529	RESULTS: Senescence markers p21(CIP1/WAF1), senescence-associated ss-galactosidase (SA-ss-gal), and p16(INK4a) were increased 2-, 8-, and 20-fold (n = 5 to 7; p < 0
27126529	Inactivation of the premature senescence program by genetic ablation of p53 and p16(INK4a) (Trp53(-/-)Cdkn2a(-/-) mice) resulted in aggravated fibrosis after transverse aortic constriction, when compared with wild-type control subjects (49 +/- 4
27115165	P16 expression was detected using western blot
27115165	Western blot confirmed that P16 expression was significantly increased in RPE cells of aged SAMP8 mice
27092462	Furthermore, stromal cells senescence was through p53 and p16 pathways
27048913	Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14(ARF)
27036204	Senescence biomarkers, including p53, p21, and p16, were upregulated in P6 cells relative to P3 cells
27029014	Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife
27029014	BACKGROUND: The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21
27029014	Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age
27029014	OBJECTIVE: The aim of this study was to examine the immunolocalization pattern of p16ink4a in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral correlate of cognitive decline in late midlife
27029014	LSG biopsies were analyzed by qRT-PCR for the expression level of p16ink4a
27029014	RESULTS: p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells
27029014	The mean relative expression of p16ink4a in LSGs was higher in the group of participants with decline in cognitive performance
27029014	A logistic regression analysis revealed that the relative p16 expression was predictive of the participant's group assignment
27029014	A negative correlation was found between relative p16ink4a expression and the participant's standardized regression residuals from early adulthood to late midlife cognitive performance scores
27029014	CONCLUSIONS: p16ink4a expression in human LSGs may constitute a potential peripheral correlate of cognitive decline
27000748	Entry into the presenescent state results from loss of autophagy, leading to increased ROS and epigenetic modification at the CDKN2A locus due to decreased H2Aub, upregulating cell senescence biomarker p16ink4a
26997276	Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation
26990999	Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP)
26983960	Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health
26983960	The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated beta-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue
26961881	In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF
26961881	Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence
26950362	The senescence effector p16(Ink4a) is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized
26950362	We found that beta cell-specific activation of p16(Ink4a) in transgenic mice enhances glucose-stimulated insulin secretion (GSIS)
26950362	Expression of p16(Ink4a) in beta cells induces hallmarks of senescence--including cell enlargement, and greater glucose uptake and mitochondrial activity--which promote increased insulin secretion
26950362	GSIS increases during the normal aging of mice and is driven by elevated p16(Ink4a) activity
26950362	We found that islets from human adults contain p16(Ink4a)-expressing senescent beta cells and that senescence induced by p16(Ink4a) in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-gamma proteins
26943583	A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-beta-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy
26941359	Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated beta-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression
26909594	GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells
26899446	A similar miRNA alteration was observed in senescent fibroblasts in vitro, and the age-related miRNA profile may interact with p16 pathway to regulate the fibroblasts' senescence
26883501	Endothelial cells and pericytes from BubR1(H/H) mice had increased senescent-associated beta-galactosidase activity and p16(INK4a) expression, demonstrating an exacerbation of senescence
26868148	SCF(Fbxo22)-KDM4A is required for the induction of p16 and senescence-associated secretory phenotypes during the late phase of senescence
26866709	Senescence is considered a tightly regulated stress response that is largely governed by the p53/p21 and p16/Rb pathways
26860864	A further paradox revolves around the observation that, while cell senescence should inhibit proliferation, the senescence marker p16INK4a correlates with poor treatment outcome in patients with a very aggressive triple-negative breast carcinoma (TNBC)
26860864	In addition, polyploid cells were positive for markers of embryonic stemness (OCT4, SOX2, NANOG) and senescence (p16INK4a)
26847209	In addition, compared with wild-type MEFs or MEFs with a single gene deficiency, BubR1(+/-) SGO1(+/-) MEFs expressed enhanced levels of p21 but not p16
26843058	Increased expression of senescence markers p14(ARF) and p16(INK4a) in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome
26843058	Univariate comparison showed a correlation between high p16(INK4a) expression and poor survival (P = 0
26843058	Multivariate analysis showed p16(INK4a) to be an important prognostic factor for overall survival (P = 0
26843058	Moreover, patients showing both high p16(INK4a) expression and and high p14(ARF) expression had an adjusted three-fold increased risk of disease recurrence (P < 0
26843058	CONCLUSIONS: These finding suggest p16(INK4a) expression and p14(ARF) expression may play an important role in the progression of proliferative breast tissue to invasive cancer, and may be useful as prognostic factors
26840489	Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing
26839109	RESULTS: SA-beta-Gal positivity was observed obviously in mice corneal endothelium of allogenic group and the levels of p16(INK4a) message and protein increased in endothelium of allogenic group compared to syngenic group
26839109	We also developed an in vitro experimental model using H2O2 treatment to simulate a state of oxidative stress in cultured human corneal endothelial cells (HCECs) and found that elevated ROS levels, the up-regulation of CDK inhibitors and ROS-mediated p16(INK4A) up-regulation in HCECs occur via the ASK1-p38 MAPK pathway
26809688	In addition, we show signs of DNA damage and aging such as gammaH2AFX and CDKN2A expression in the respiratory epithelia of infected mice long after viral clearance
26763147	Expression of hCMV immediate early (IE) and early (E) proteins and senescence-associated proteins (pRb and Rb, p16(INK4), and p53) and production of reactive oxygen species (ROS) were assessed using standard laboratory assays
26731175	Tenofovir/emtricitabine metabolites and endogenous nucleotide exposures are associated with p16(INK4a) expression in subjects on combination therapy
26731175	We determined associations of frailty phenotype, a T-cell senescence marker (p16(INK4a) expression), age and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV)
26731175	Subjects underwent frailty phenotyping and p16(INK4a) expression analysis
26731175	Negative associations were observed between p16(INK4a) expression and each of FTC-triphosphate (r=-0
26731175	CONCLUSIONS: Associations of IM/EN exposure and p16(INK4a) expression observed here suggest that senescence may alter drug phosphorylation, metabolism or transport
26721440	Examination of the causal relationship between pNO40 deficiency and MSC-accelerated aging revealed big up tri, openE4 null disruption in MSCs elicits high levels of ROS and elevated expression levels of p16 and Rb but not p53
26718972	Absence of AMPKalpha2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts
26718972	The aim of this study was to determine if AMPKalpha deletion contributes to the accelerated cell senescence by inducing p16(INK4A) (p16) expression thereby arresting cell cycle
26718972	It was shown here that AMPKalpha2 deletion upregulates cyclin-dependent kinase (CDK) inhibitor, p16, which arrests cell cycle
26718972	Interestingly, knockdown of HMG box-containing protein 1 (HBP1) partially blocked the cellular senescence of AMPKalpha2-deleted MEFs via the reduction of p16
26718972	Finally, dermal cells senescence, including fibroblasts senescence evidenced by the staining of p16, HBP1, and Ki-67, in the skin of aged AMPKalpha2(-/-) mice was enhanced when compared with that in wild type mice
26717900	Cellular senescence is a state of irreversible growth arrest that can be triggered by multiple mechanisms, including telomere shortening, the epigenetic derepression of the INK4alpha/ARF locus and DNA damage
26708220	Notably, silencing ANRIL did not result in the activation of expression of the INK4 locus
26696133	In addition, the levels of some senescence-associated proteins, such as phosphorylated ERK1/2, caveolin-1, p53, p16(ink4a), and p21(waf1), were elevated in PPKO-treated cells
26683595	Following inhibition of ASPH activity, phosphorylation of glycogen synthase kinase 3beta and p16 expression were increased to promote senescence, whereas cyclin D1 and proliferating cell nuclear antigen were decreased to reduce cell proliferation
26663487	We show that SNEV(P) (rp19/) (PSO) (4) expression decreases during organismal ageing, while p16, a marker of ageing in vivo, increases
26663487	In old SNEV(P) (rp19/) (PSO) (4) mice, this increase is accompanied by reduced epidermis thickening and increase in p16 and collagenase levels
26654351	Senescence-associated beta-galactosidase (SA-beta-Gal) activity and aging-associated p16 (cyclin-dependent kinase inhibitor 2A) expression were also quantified
26654351	SA-beta-Gal activity and p16 expression were increased in aged cells compared with young ones and in siRNA SIRT6 knockdown cells compared with their controls
26654351	Downregulation of SIRT6 in these cells resulted in less cell proliferation and migration but increased SA-beta-Gal activity and p16 expression
26629698	Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus
26589970	Whereas the increased p16 expression and SAHF were concomitant with that of beta-galactosidase, those of p53 and p21 were barely detected
26589970	Our findings showed that in hepatocarcinogenesis by diethylnitrosamine, cellular senescence is associated with p16 pathway activation and is mainly localized in myofibroblast-like cells
26583757	By screening a library of activated kinases, we identified 33 kinases whose constitutive expression decreases cell proliferation and induces expression of senescence markers; p16 and SASP components
26583057	GOx induced senescence, increasing senescence associated beta-galactosidase activity and the expression of p16
26583057	Ectopic overexpression of ILK in cells increased p16 expression, even in the absence of GOx, whereas downregulation of ILK inhibited the increase in p16 due to oxidative stress
26583057	We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex
26528855	Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
26528855	Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a
26528855	Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors
26503169	We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb
26500063	The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes
26500063	Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype
26477465	Although cancer cells frequently possess mutations in two main signalling pathways involved in cell senescence, namely p53/p21 and p16/Rb, they still preserve the ability to undergo DNA damage-induced senescence
26476632	In the aorta, RBEE treatment reduced expression of the apoptosis pathway components p16, p53 and bax/bcl-2 ratio
26467393	Seven/eight nephrectomized rats feeding a hyperphosphatemic diet and fifteenth- month old mice showed hyperphosphatemia and aortic ILK, p53 and p16 expression
26466127	We have found that in the diabetic retinas there was an up-regulation of senescence-associated markers SA-beta-Gal, p16INK4a and miR34a, which correlated with decreased expression of SIRT1, a target of miR34a
26439691	The ING1a epigenetic regulator synchronously induces senescence in mass cultures several-fold faster than all other agents, taking 24 and 36 hours to activate the Rb/ p16INK4a, but not the p53 tumor suppressor axis to efficiently induce senescence
26412380	ARF: connecting senescence and innate immunity for clearance
26412380	We have found evidence suggesting that ARF and p53 are essential for tumor regression upon MYC inactivation through distinct mechanisms ARF through p53-independent affect, is required to for MYC to regulate the expression of genes that are required for both the induction of cellular senescence as well as recruitment of innate immune activation
26404840	Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins
26404840	GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a)
26391655	Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence
26386262	For example, CDKN2A, the best-known melanoma susceptibility gene, encodes two effectors of cell senescence, while other familial melanoma genes are related to telomeres and their maintenance
26381124	We also identify germline genetic variants, including those associated with the p16INK4A locus, which are associated with the presence of in vivo senDMP signatures
26372907	Cellular senescence in four WAT depots was assessed using senescence-associated beta-galactosidase staining to quantify the senescent cell burden, and real-time qPCR to quantify gene expression of senescence markers p16 and IL-6
26365380	Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a)
26365380	We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes
26365380	Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas
26336034	We tested whether one night of partial sleep deprivation (PSD) would increase leukocyte gene expression indicative of DNA damage responses (DDR), the senescence-associated secretory phenotype (SASP), and senescence indicator p16(INK4a) in older adult humans, who are at increased risk for cellular senescence
26336034	The senescence marker p16(INK4a) (CDKN2A) was increased 1day after PSD compared to baseline (p<
26331977	We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence-associated secretory phenotype (SASP) and other senescence-associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence
26299965	Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16
26292757	An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress
26292757	Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression
26292757	We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21(Cip1) and p27(Kip1) proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors
26286607	Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders
26286607	The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age
26286607	Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology
26277387	Whereas p21(CIP1/WAF1) was highest in old G1 and G4 Terc(-/-), telomere shortening and p16(INK4a) expression, also significantly associated with later generation young Terc(-/-), were not further induced in old Terc(-/-) mice
26277387	While these aspects resemble the situation seen in aged human kidneys, the lack of telomere shortening and p16(INK4a) induction in older Terc(-/-) animals differs from observations in old human kidneys and may result from clearance of senescent cells
26240351	Concomitantly, increased cellular senescence in the adipose tissue from pol eta(-/-) mice was observed and measured by up-regulation of senescence markers, including p53, p16(Ink4a), p21, senescence-associated (SA) beta-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) as early as 4 wk of age
26224580	On a negative side, statins impaired the osteogenic and chondrogenic differentiation potential of MSCs and increased cell senescence and apoptosis, as indicated by upregulation of p16, p53 and Caspase 3, 8, and 9
26215037	Western blot was used to assess SHP-1, p21, p53, pRb, Rb, H3K9Me3, HP1gamma, CDK4, cyclin D1, cyclin E, and p16 protein expressions
26199639	Moreover, bavachalcone suppressed senescence in human endothelial cells and mRNA expression of p16(ink4a) (a marker of replicative senescence) and IL-1alpha (a proinflammatory cytokine of the senescence-associated secretory phenotype)
26199387	Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome
26199387	We hypothesized that CS mechanisms may have potential prognostic relevance in cHL and investigated whether the expression of the well-established CS biomarkers p21(CIP1/WAF1) and p16(INK4a) by HRS cells might be predictive of the probability of event-free survival (EFS)
26199387	The presence or the lack of the robust expression of p21(CIP1/WAF1) and/or p16(INK4a) defined the prognosis in our series
26199387	CONCLUSIONS: These findings point to (i) the relevance of CS-related mechanisms in cHL, and to (ii) the prognostic value of a simple, reproducible, and low-cost immunohistochemical evaluation of p16(INK4a) and p21(CIP1/WAF1) expression
26195892	The effects of short-term hypoxia on human mesenchymal stem cell proliferation, viability and p16(INK4A) mRNA expression: Investigation using a simple hypoxic culture system with a deoxidizing agent
26195892	Interestingly, the p16(INK4A) expression altered proportionately to the O2 concentration
26168818	Statistically significant increase of senescence associated beta-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals
26168478	Transcriptional Regulation of the p16 Tumor Suppressor Gene
26168478	The p16 tumor suppressor gene encodes a specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 and is found altered in a wide range of human cancers
26168478	Polycomb group (PcG) proteins associate with the p16 locus in a long non-coding RNA, ANRIL-dependent manner, leading to repression of p16 transcription
26168478	YB1, a transcription factor, also represses the p16 transcription through direct association with its promoter region
26168478	Conversely, the transcription factors Ets1/2 and histone H3K4 methyltransferase MLL1 directly bind to the p16 locus and mediate p16 induction during replicative and premature senescence
26168478	In the present review, we discuss the molecular mechanisms by which these factors regulate p16 transcription
26140238	NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16INK4a and nuclear translocation of p-HP1gamma, and permanent arrest of cancer cell proliferation
26112217	Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway
26102294	Accordingly, failure of autophagy was accompanied by an accumulation of p16ink4a, nuclear disintegration, and loss of cell recovery
26094870	Simultaneous examination of p16(INK4A) expression, which predicts tumours that have bypassed cellular senescence, revealed that intermediate levels of p16(INK4A) correlate with an intact pRB pathway and improved survival
26094870	A combination of these master transcriptional regulators and p16(INK4A), termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy
26089914	High OCT4 and Low p16(INK4A) Expressions Determine In Vitro Lifespan of Mesenchymal Stem Cells
26089914	For each early passage BM-MSC sample (5th or 6th passages), the normalized protein expression levels of senescence-associated markers p16(INK4A), p21(WAF1), SOD2, and rpS6(S240/244); the concentration of IL6 and IL8 in cell culture supernatants; and the normalized gene expression levels of pluripotency markers OCT4, NANOG, and SOX2 were correlated with final population doubling (PD) number
26089914	We revealed that the low expression of p16(INK4A) protein and a high OCT4 gene expression, rather than other evaluated markers, might be potential hallmarks and predictors of greater in vitro lifespan and growth potential, factors that can impact the successful therapeutic use of MSCs preparations
26004298	Enhancer of zeste homolog 2 depletion induces cellular senescence via histone demethylation along the INK4/ARF locus
26004298	In gastric cancer cells, INK4/ARF locus was activated to certain extent in consequence of a decrease of H3K27me3 along it caused by EZH2 silence, which contributed substantially to an increase in the expression of p15(INK4b), p14(ARF) and p16(INK4a) and resulted in cellular senescence ultimately
26004298	Furthermore, MKN28 cells, which did not express p16(INK4a) and p21(cip), could be induced to senescence via p15(INK4b) activation and suppression of p15(INK4b) reversed senescence progression induced by EZH2 downregulated
26004298	These data unravel a crucial role of EZH2 in the regulation of INK4/ARF expression and senescence procedure in gastric cancer cells, and show that the cellular senescence could just depend on the activation of p15(INK4b)/Rb pathway, suggesting the cell-type and species specificity involved in the mechanisms of senescence inducement
25994420	Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells
25994150	MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway
25993799	Expression of aging-related p53, p21, p16, Rb mRNA and P16, Rb, CDK4 and Cyclin E protein were detected by quantitative reverse transcription polymerase chain reaction( qRT-PCR) and Western blotting, respectively
25993799	Aging-related p53, p21, p16, Rb and P16, Rb were up-regulated, protein regulatory cell-cycle CDK4 and Cyclin E were down-regulated
25991604	Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated beta-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations
25967604	Furthermore ASMq up-regulated the tumor suppressor genes p21, p53 and p16 and down-regulated the micro-RNAs hsa-mir-17 and hsa-mir-106b
25924011	A significant increase in phosphorylation of gamma-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected
25924011	Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-beta-gal activity, gamma-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels
25923845	Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice
25923845	The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing
25923845	However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear
25923845	Here we show that, in mutant mice homozygous for a hypomorphic allele of the alpha-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation
25923845	Surprisingly, this is due to the restoration of alpha-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in alpha-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of alpha-klotho expression
25923845	Indeed, p16(INK4a) represses alpha-klotho promoter activity by blocking the functions of E2Fs
25923845	These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of alpha-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating alpha-klotho expression during ageing
25895748	Protein expression relating to apoptosis (Bax, Bcl-2, Survivin), autophagy (Beclin-1, LC3B) and cellular senescence (p21, p16) was evaluated using indirect immunofluorescence
25895748	Biopsies of CXPA (ex vivo) allowed immunhistochemical evaluation of p21 and p16, whilst LC3B, p21 and p16 protein expression was analyzed by western blotting
25895748	In the in vitro model, the myoepithelial cells were positive for LC3B (cytoplasm) and p21 (nucleus), whilst in vivo positivity for p21 and p16 was observed
25895748	Western blotting analysis revealed an increased LC3B, p16 and p21 expression in the myoepithelial cells with previous contact with the malignant cells when compared with those without contact
25882843	Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated beta-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs
25879533	Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage
25876105	RESULTS: GLB1 expression accumulates in replicative and induced senescence and correlates with senescent morphology and P16 (CDKN2) expression
25869441	Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised
25840344	Finally, we found that the level of p16INK4A expression significantly increased supporting cellular senescence process associated to our model
25839657	Intracellular ROS levels were increased in hBM-MSCs; this was accompanied by a decrease in the expression of the antioxidant enzymes catalase and superoxide dismutase (SOD)1 and 2 and of phosphorylated forkhead box O1 (p-FOXO1) as well as an increase in the expression of p53 and p16, along with a reduction in differentiation potential
25832744	Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16(Ink4a)
25832744	Using real-time in vivo imaging of p16(Ink4a) expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16(Ink4a) pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity
25826898	OBJECTIVE: To investigate the expression of p16INK4a in nucleus pulposus (NP) and to clarify its relationship with intervertebral disc degeneration so as to provide evidence for biological repair of intervertebral disc
25826898	Senescence marker (p16INK4a) and disc degeneration markers [A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5), Aggrecan, and Sry-related HMG box transcription factor 9 (Sox-9)] were determined in the NP specimens with immunohistochemistry and Western blot
25826898	The correlation between ADAMTS 5 and p16INK4a was analyzed
25826898	The NP with grade IV degeneration showed significantly higher protein expressions of p16INK4a and ADAMTS 5 (P < 0
25826898	Importantly, there was a good correlation between p16INK4a and ADAMTS 5 protein expressions (r=0
25826898	The expression of p16INK4a and its association with degeneration grades suggest that the p16INK4a may play a significant role in the pathogenesis of intervertebral disc degeneration
25820160	Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor
25819580	The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting
25819580	Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated beta-galactosidase (SA-beta-Gal)-positive chondrocytes; it also led to increased p16 levels
25815136	The hypoxic micro-environment turns on hypoxia-inducible factor-1 to prevent mesenchymal stem cells aging through p16 and p21 down-regulation
25804560	DESIGN: The relationship between sphere formation and the degree of cellular senescence was investigated by analysing senescence-associated beta-galactosidase activity and the expression of senescence-related markers such as CDKN2A (p16) and p21
25804560	In addition, the expression of p16 and p21 proteins tended to be lower in the Y-27632 group
25784651	Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications
25772242	The Ink4a-Arf locus (also known as Cdkn2a), which encodes p16(INK4A) and p19(ARF), has a central role in inducing and maintaining senescence
25766527	In particular, Gas6-treated cells displayed decreased staining for SA-beta-Gal, fewer G1 phase cells, and decreased levels of p16(INK4a) and p21(Cip1) expression; conversely, Gas6-treated cells displayed more S phase cells and significantly increased proliferation indexes
25760322	The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation
25754218	Senescence associated beta-galactosidase activity and the expression of p16 and p21 were increased, whereas phosphorylated retinoblastoma protein was reduced
25728679	Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of beta-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways
25695870	Although much is known about the key players in the implementation of senescence, including the pRb and p53 axes and the cyclin dependent kinase inhibitors p16(INK4a) and p21(CIP1), many details remain unresolved
25695870	At the permissive temperature, where pRb and p53 are functionally compromised by T-Ag, cyclin D-CDK4 complexes are disrupted by the high p16(INK4a) levels and reduced expression of p21(CIP1)
25684390	Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A
25683165	Sirtuin 6 in turn abrogated the inducing effect of TGF-beta1/H2O2/HOCl on cellular senescence of HCC cells, and was required for the ERK pathway to efficiently suppress the expression of p16 and p21
25678367	Immunohistochemical Expression of p16 and p21 in Pituitary Tissue Adjacent to Pituitary Adenoma versus Pituitary Tissue Obtained at Autopsy: Is There a Difference
25678367	The purpose of this study was to investigate differences in p16 and p21 immunohistochemical expression in normal pituitary tissue adjacent to pituitary adenoma obtained during neurosurgical procedure with pituitary tissue obtained at autopsy, from patients who died from non-endocrinological diseases
25678367	Our results show significant difference in p16 nuclear and p21 cytoplasmic immunohistochemical expression between two types of normal pituitary tissues
25678367	Our finding that differences are probably not influenced by postmortem changes is supported by no significant correlation between postmortem interval and immunohistochemical p16 and p21 expression
25675863	We found a significantly increased expression of p16(INK4A) in BCP-ALLs with MLL rearrangement
25675863	Enhanced p16(INK4A) expression was only related to a significantly shorter DFS
25647436	Dermal papilla cells (DPCs) taken from male androgenetic alopecia (AGA) patients undergo premature senescence in vitro in association with the expression of p16(INK4a), suggesting that DPCs from balding scalp are more sensitive to environmental stress than nonbalding cells
25647436	At 21% O2, DPCs showed flattened morphology and a significant reduction in mobility, population doubling, increased levels of reactive oxygen species and senescence-associated beta-Gal activity, and increased expression of p16(INK4a) and pRB
25640160	The p16 gene displayed similar ASncmtRNA-2 expression patterns, suggesting a possible co-regulation of the two genes
25622904	Sag inactivation by genetic deletion remarkably suppresses cell proliferation by inducing senescence, which is associated with accumulation of p16, but not p53
25622904	Mechanistically, Sag deletion caused accumulation of Jun-B, a substrate of Sag-Fbxw7 E3 ligase and a transcription factor that drives p16 transcription
25622904	Importantly, senescence triggered by Sag deletion can be largely rescued by simultaneous deletion of Cdkn2a, the p16 encoding gene, indicating its causal role
25622904	Furthermore, Kras(G12D)-induced immortalization can also be abrogated by Sag deletion via senescence induction, which is again rescued by simultaneous deletion of Cdkn2a
25622904	Finally, we found that Sag deletion inactivates Kras(G12D) activity and block the MAPK signaling pathway, together with accumulated p16, to induce senescence
25601475	A vlincRNA participates in senescence maintenance by relieving H2AZ-mediated repression at the INK4 locus
25601475	VAD modulates chromatin structure in cis and activates gene expression in trans at the INK4 locus, which encodes cell cycle inhibitors important for senescence-associated cell proliferation arrest
25601475	Z at INK4 gene promoters in senescent cells
25594009	Senescence was associated with inhibition of phosphorylated/active p65-NFkB and induction of the cell cycle inhibitor, p16(ink4a)
25593054	AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16
25582187	Additionally, p16 gene plays a critical role in controlling aging, regulating cellular senescence, detection and maintenance of DNA damage
25582187	The molecular mechanism behind these events involves p16-mediated signaling pathway (or p16- Rb pathway), the focus of our study
25582187	We implement experimental data from the literature to validate the model, and under various assumptions predict the dynamic behavior of p16 and other biological components by interpreting the simulation results
25567807	In the renal tissues of Type 2 DN patients, we detected an increased number of senescent cells; elevated deposition of advanced glycation end products (AGEs); upregulated expression of ER stress marker, glucose-regulated protein 78; as well as overexpression of ATF4 and p16
25567807	Interestingly, AGE-induced p16 expression and premature senescence were successfully attenuated by ER stress inhibitor and ATF4 gene silencing
25567807	Moreover, AGE-induced premature senescence was mimicked by ER stress inducers and ATF4 overexpression, while suppressed by p16 gene silencing
25540416	EBNA3A and EBNA3C jointly suppress p16(INK4A) and p14(ARF), enabling continuous cell proliferation
25540416	EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1
25515777	Patz1(+/-) MEFs can surpass the senescence barrier of Ink4a/Arf locus, thus enhancing iPS colonies formation
25515777	However, Patz1(-/-) MEFs gave the lowest reprogramming efficiency which may result from cell senescence trigged by up-regulated Ink4a/Arf locus
25511229	CKD rats showed increased protein expression of senescence-associated beta-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders
25501747	Here, we show that the exogenous and endogenous expression of an oncogenic form of small GTPase Ras (called oncogenic Ras) decrease the expression of lncRNA ANRIL (antisense non-coding RNA in the INK4 locus), which is involved in the regulation of cellular senescence
25485497	Global gene expression analyses uncovered an induction of p16(INK4a) in satellite cells of physiologically aged geriatric and progeric mice that inhibits satellite cell-dependent muscle regeneration
25485497	Aged satellite cells lose the repression of the INK4a locus, which switches stem cell reversible quiescence into a pre-senescent state; upon regenerative or proliferative pressure, these cells undergo accelerated senescence (geroconversion), through Rb-mediated repression of E2F target genes
25485497	Here we discuss on how cellular senescence may be a common mechanism of stem cell aging at the organism level and show that induction of p16(INK4a) in young muscle stem cells through deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype
25482089	Compared with normal pituitary cells, the aging pituitary tissues revealed increased expression of IL6, C/EBPbeta, p53, p21 and p16 and decreased expression of pituitary tumor transforming gene
25482089	In contrast, the expression of IL6, p21 and p16 was decreased in pituitary tumor cells compared with normal pituitary tissues
25482089	Taken together, multiple pathways including IL6/C/EBPbeta, p53/p21 and p16 were activated in aging pituitary cells in response to Dgal treatment
25481981	Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a
25481981	The cyclin-dependent kinase (Cdk) inhibitor p16(Ink4a) (p16) is a canonical mediator of cellular senescence and accumulates in aging tissues, where it constrains proliferation of some progenitor cells
25481981	However, whether p16 induction in tissues is sufficient to inhibit cell proliferation, mediate senescence, and/or impose aging features has remained unclear
25481981	To address these issues, we generated transgenic mice that permit conditional p16 expression
25481981	Aging features were observed with multiple combinations of p16 transgenes and transactivators and were largely abrogated by a germline Cdk4 R24C mutation, confirming that they reflect Cdk inhibition
25481981	Senescence markers were not found, and de-induction of p16, even after weeks of sustained expression, allowed rapid recovery of intestinal cell proliferation and reversal of aging features in most mice
25461770	A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate
25461770	This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a
25437179	When compared with N-UC-MSCs, GDM-UC-MSCs showed decreased cell growth and earlier cellular senescence with accumulation of p16 and p53, even though they expressed similar levels of CD105, CD90, and CD73 MSC marker proteins
25411512	PURPOSE: To determine whether p16, a molecular marker of cellular senescence, and CD68, a microglial marker, are detectible in optic nerve glioma tissue stored for decades, thus providing potential targets for pharmacologic intervention
25411512	Immunoreactivity for p16 protein was seen in 36 cases (75%) and CD68-positive cells in 34 (71%)
25411512	Immunoreactivity for p16 protein and CD68 is positive in the majority
25385658	The expression of p16INK4a, a marker of cellular senescence, was examined by immunofluorescence staining and western blot analysis
25384549	In this study, we showed that NaDC3 overexpression accelerated cellular senescence in young human diploid cells (MRC-5 and WI-38) and primary renal tubular cells, leading to cell cycle arrest in G1 phase and increased expression of senescent biomarkers, senescence-associated beta-galactosidase and p16
25364077	Senescence markers showed reduced TERT and cyclin A and increased p16INK4a expression, with higher IL-6 plasma levels in SF-exposed mice
25359865	APPROACH AND RESULTS: When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages
25331947	Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFkappaB
25331947	Furthermore, we have observed increased NFkappaB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression
25331947	Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0
25331947	Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors
25331947	However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors
25331947	These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFkappaB
25328137	Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1)
25311168	In addition, increased expression of CDKN2A and its transcriptional activators ETS1 and ARHGAP18 (SENEX) along with decreased expression of CDKN2A inhibitor ID1 were detected in FECD samples
25310478	Following serial passaging, rat MSCs underwent replicative senescence, characterized by positive staining for senescence-associated beta-galactosidase (SA-beta-gal), and increased expression levels of p16 and p21
25289642	Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile ductular tumors and lesions
25289642	Given overexpression of a polycomb group protein EZH2 in intrahepatic cholangiocarcinoma and high expression of senescence-associated p16INK4a in ductular reactions, we plan to apply immunostaining for EZH2 and p16INK4a for differential diagnosis of these bile ductular tumors/lesions
25289642	In contrast, the expression of p16INK4a was seen in most bile duct adenomas and all ductular reactions, whereas it was barely seen in cholangiolocellular carcinomas
25289642	A borderline between cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16INK4a
25289642	In conclusion, immunostaining for EZH2 and p16INK4a may be useful for differential diagnosis for bile ductular tumors/lesions
25277993	Ageing as developmental decay: insights from p16(INK4a
25277993	Detailed examination of the pathways regulating p16(INK4a) expression has revealed an overlap with those regulating early development
25277993	To support this, we summarise the role of p16(INK4a) in ageing and our current knowledge on p16(INK4a) regulation
25264199	FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis
25264199	CDKN2A (p16(INK4a)) is a crucial tumor suppressor involved in many cancers
25264199	Our recent investigations revealed that FOXA1 as a forkhead transcription factor mediates CDKN2A activation in cellular senescence
25264199	Here, using a comprehensive collection of cancer microarray data, we found FOXA1 is down-regulated in many cancers compared to their normal counterparts and the positive correlation between FOXA1 and CDKN2A could be observed in prostate and breast cancers with lower EZH2 (epigenetic repressor for CDKN2A) expression
25264199	Experimentally, epistasis analysis in prostate and breast cancer cells indicated that higher expression of FOXA1 opposes EZH2-mediated CDKN2A repression, as further depletion of FOXA1 reverts the de-silencing of CDKN2A caused by EZH2 inhibition
25264199	Concomitantly, EZH2-depletion suppresses cancer cell cycle progression and this regulation is optimized in the presence of FOXA1 and CDKN2A
25264199	A further oncogenic transformation assay suggested that overexpression of EZH2 is insufficient to block RAS-induced CDKN2A activation and loss of FOXA1 is mandatory to potentiate EZH2-mediated CDKN2A silencing and to bypass the senescence barrier
25264199	These data support that positive regulation of CDKN2A by FOXA1 counteracts its tumorigenic repression of by EZH2 in cancers
25263442	The Polycomb group protein Bmi-1 is an essential regulator of cellular senescence and is believed to function largely through the direct repression of the Ink4a/Arf locus
25263442	However, concurrent deletion of Ink4a/Arf does not fully rescue the defects detected in Bmi-1(-/-) mice, indicating that additional Bmi-1 targets remain to be identified
25241737	This is due to repressed expression of p16(INK4a), which, in turn, delays MaSC senescence
25229346	Tissue taurine depletion in taurine transporter knockout (TauTKO) mouse was found to shorten lifespan and accelerate skeletal muscle histological and functional defects, including an increase in central nuclei containing myotubes, a reduction in mitochondrial complex 1 activity and an induction in an aging biomarker, Cyclin-dependent kinase 4 inhibitor A (p16INK4a)
25218945	Specific, validated markers can identify senescent cells, including senescence-associated beta galactosidase activity, chromatin alterations, cell morphology changes, activated p16- and p53-dependent signaling and permanent cell cycle arrest
25216853	Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence
25203674	Treatment of LNCaP cells with AA is associated with hypophosphorylation of the retinoblastoma tumor suppressor and an increase of p16 expression, whereas the p53-p21 signaling pathway seems not be affected by AA treatment
25203674	Analyzing human PCa tissue samples treated with AA ex vivo also indicates an induction of cellular senescence associated with an increase of p16 expression but not p21
25188864	Immunohistochemistry showed that the EC cells always expressed p16, a senescence-associated marker, and had a significantly lower Ki-67 labeling index than adjacent cuboidal and columnar cells (P=0
25188864	Senescence was further established by markers such as SA-beta-gal staining, expression of p16 and p21, and reduction in DNA synthesis
25181340	Reactive oxygen species promotes cellular senescence in normal human epidermal keratinocytes through epigenetic regulation of p16(INK4a
25181340	The expression of cyclin-dependent kinase (CDK) inhibitors, especially p16(INK4a) was upregulated in NHEKs treated with H2O2
25181340	Interestingly, H2O2 suppressed the methylation of p16(INK4a), promoter region in NHEKs, but not in SCCs
25181340	Our results indicate that the ROS-induced cellular senescence in NHEKs was caused by the upregulation p16(INK4a) through demethylation in its promoter region, which is not detected in SCCs, suggesting that ROS-induced cellular senescence contributes to tumor suppression of NHEKs
25106938	Expression of senescence-associated genes p21, p16, and interleukin 6 (IL6) were also assessed
25057072	CONCLUSION: Silencing Bmi-1 by RNA interference can induce cell senescence and resensitize A549/DDP cells to cisplatin possibly by regulating INK4a/ARF/Rb senescence pathway
25043688	We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry
25043688	Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex
25043688	An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol
25043688	After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated beta-galactosidase activity
24981831	The mechanisms underlying the senescence growth arrest are broadly considered to involve p16(INK4A) -pRB and p53-p21(CIP1/WAF1/SDI1) tumor suppressor pathways; but it is not known what makes the senescence arrest stable and what the critical downstream targets are, as they are likely to be key to the establishment and maintenance of the senescent state
24950189	Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells
24934810	Furthermore, MYC activation leads to reduced expression of the senescence markers p16(INK4A), p21(CIP1), and H3K9me3-containing heterochromatin foci, and an increased percentage of Ki67(+) tumor cells
24934810	However, these tumors were of smaller size, showed increased expression of p16(INK4A) and p21(CIP1), and reduced number of Ki67(+) cells, indicating that MYC inactivation restores BRAF(V600E)-induced senescence
24934763	Moreover, depletion of p16(Ink4a) and p19(Arf) involved in the activation of cellular senescence is sufficient to convert human fibroblast and epithelial cells into neurons
24931169	Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation
24925089	Conversely, JMJD3 displaces polycomb complexes from the INK4 box, which induces the expression of INK4a and triggers cellular senescence
24925089	The control of INK4 box and p53 is closely related to the regulation of the aging process
24832598	BLM-, WRN- and RECQL4-depleted cells display increased staining of senescence-associated beta-galactosidase (SA-beta-gal), higher expression of p16(INK4a) or/and p21(WAF1) and accumulated persistent DNA damage foci
24827852	RESULTS: The irradiated livers displayed several markers of cell senescence, including expression of senescence-associated-beta-galactosidase (SA-beta-gal), increase in cell size, and up-regulation of cyclin-dependent kinase inhibitors (CDK-I) p16 and p21
24807532	Furthermore, upregulation of p16(INK4a) was critical to the antitumor activity of HepG2 cells treated with fucoidan and was correlated with inhibition of Cdk4 and pRb and upregulation of p21 expression
24807532	Moreover, it prevents cellular senescence of Chang-L cells, by decreasing p14(Arf) expression as cells enter quiescence, with the reduction of p16(INK4a)
24752601	Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction
24752601	Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation
24747969	MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway
24747969	Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2
24681605	BACKGROUND: Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology
24681605	To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy
24681605	Expression of senescence markers p16 (INK4a) and ARF mRNA was determined using TaqMan quantitative reverse-transcription polymerase chain reaction in CD3(+) T lymphocytes, telomere length was determined by Southern analysis, and senescence-associated cytokines were determined by enzyme-linked immunosorbent assay
24681605	RESULTS: In prospectively analyzed patients, expression of p16 (INK4a) and ARF increased immediately after chemotherapy and remained elevated 12 months after treatment
24681605	Median increase in log2 p16 (INK4a) was 0
24681605	ARF expression was comparably increased (P <
24681605	Increased expression of p16 (INK4a) and ARF was associated with dose-dense therapy and hematological toxicity
24681605	In a cross-sectional cohort, prior chemotherapy exposure was independently associated with a log2-increase in p16 (INK4a) expression of 0
24676500	X and p16(INK4A) were also increased in DPSCs with repeated LPS stimulation
24676500	We found that the LPS bound with Toll-like receptor 4 (TLR4) and that TLR4 signaling accounted for p16(INK4A) expression
24676500	Further results indicated that the senescence of DPSCs stimulated repeatedly with LPS was reversed by p16(INK4A) short interfering RNA
24676500	The DNA damage response and p16(INK4A) pathways might be the main mediators of DPSC senescence induced by repeated LPS stimulation
24672805	Role of Ink4a/Arf locus in beta cell mass expansion under physiological and pathological conditions
24672805	The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53
24672805	In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus
24672805	We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation
24672805	Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development
24672805	Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin
24667034	The p19INK4d, a member of the family of cyclin-dependent kinase inhibitors (INK4), plays an important role on cell cycle regulation and in the cellular DNA damage response
24659628	With aging, p85alpha, IGF-1 and B-myb muscle levels were lower while the expression of certain cell arrest proteins (p53, p16 and pRB) increased
24648336	Forced expression of miR-335 resulted in early senescence-like alterations in hMSCs, including: increased SA-beta-gal activity and cell size, reduced cell proliferation capacity, augmented levels of p16 protein, and the development of a senescence-associated secretory phenotype
24625975	These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70
24599991	Depletion of the cdk inhibitor p16INK4a differentially affects proliferation of established cervical carcinoma cells
24599991	The cdk inhibitor and tumor suppressor p16INK4A is consistently upregulated in cervical carcinoma cells for reasons that are poorly understood
24599991	We report here that downregulation of p16INK4A gene expression in three different cervical carcinoma cell lines reduced expression of the E7 oncogene, suggesting a positive feedback loop involving E7 and p16INK4A
24599991	IMPORTANCE: This study demonstrates that the cdk inhibitor p16INK4A, frequently used as surrogate marker for transforming infections by human papillomaviruses of the high-risk group, is required for high-level expression of the E7 oncoproteins of HPV-16, HPV-18, and HPV-45 in cervical carcinoma cells
24599991	It is also demonstrated that depletion of p16INK4A induces senescence in HeLa but not CaSki or MS-751 cervical carcinoma cells
24588771	Inhibiting enhancer of zeste homolog 2 promotes cellular senescence in gastric cancer cells SGC-7901 by activation of p21 and p16
24588771	To prove that EZH2 expression contributes substantially to the change of key cell cycle regulators, we showed that p21 and p16 were activated to a certain extent upon EZH2 depletion and activation of p21 was in a p53-independent manner
24588771	Taken together, our data suggest that EZH2 depletion promotes the progression of senescence by mediating the activation of tumor suppressor genes p21 and p16, and could serve as a potential epigenetic target for gastric cancer therapy
24587053	In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners
24584199	Furthermore, knocking down HP1alpha by siRNA alleviated the delayed DNA damage response and accelerated senescence in Zmpste24(-/-) MEFs, evidenced by the rescue of the delayed gamma-H2AX foci formation, downregulation of p16, and reduction of senescence-associated beta-galactosidase activity
24573392	Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16(INK4a)
24535104	Therefore, our studies showed that RC-6 can increase p16 and p21 protein levels and induce cellular senescence in NT2 cells
24528089	Both acetylation and trimethylation of H3 were involved in replicative senescence, while the acetylation of histone H3 and H4 was predominant in premature senescence, contributing to the mRNA expression of p16
24505380	Old kidneys showed significantly more senescence as demonstrated by increased p16 (INK4a), senescence associated beta-galactosidase, and gammaH2AX(+)/Ki-67(-) cells
24487593	Immunostaining for polycomb group protein EZH2 and senescent marker p16INK4a may be useful to differentiate cholangiolocellular carcinoma from ductular reaction and bile duct adenoma
24487593	In contrast, the ductular reaction showed high expression of senescence-associated p16(INK4a)
24487593	In this study, we examined whether immunostaining for EZH2 and p16(INK4a) is useful for differential diagnosis among cholangiolocellular carcinoma, bile duct adenoma, and ductular reactions
24487593	The expressions of EZH2 and p16(INK4a) were examined immunohistochemically
24487593	The extensive expression of p16(INK4a) was seen only in 4 cases of cholangiolocellular carcinomas (12%)
24487593	In contrast, the expression of p16(INK4a) was seen in 13 cases (81%) of bile duct adenomas and in all cases of ductular reactions
24487593	The borderline between the component of cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16(INK4a) in 69% of cases
24487593	In conclusion, immunostaining for EZH2 and p16(INK4a) may be useful for differential diagnosis among cholangiolocellular carcinomas, bile duct adenomas, and ductular reactions
24487029	TBK1/IKKepsilon inhibition promoted cellular senescence by suppressing p65-NF-kappaB and inducing p16(Ink4a)
24484372	We found not only marked attenuation of E- and A-type cyclins, but also increased expression of p16 and p-p21
24481601	High extracellular levels of human recombinant Dkk1 inhibited epithelial cell growth and induced cellular senescence in vitro, as demonstrated by reduced cell proliferation, G0/G1 cell cycle arrest, elevated senescence-associated beta-galactosidase activity, and upregulation of p16
24481601	In healthy esophageal mucosa, Dkk1 expression was associated with low expression of transcriptionally active beta-catenin, while in reflux-esophagitis tissue, Dkk1 overexpression correlated with increased senescence-associated beta-galactosidase activity and p16 upregulation
24476133	We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and beta-galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS)
24471909	The expression of cell-senescence markers p16(INK4a) and p21(CIP1/WAF1) was also immunohistochemically investigated
24471909	We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16(INK4a) and p21(CIP1/WAF1) were expressed, irrespective of BRAF mutation status
24471909	Interestingly, all the aggressive cases did not express p16(INK4a), thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma
24464249	The downregulation of Skp2 is parallel with increasing p16 and p21 expression which causes G0/G1 arrest and tumor cell senescence
24449267	Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence
24441872	This was associated with activation of the senescent pathway markers p53/21 and p16
24406044	Transfection of miR-138 mimic induced SN-12 cell senescence, decreased the protein expression of EZH2, and increased the protein expression of P16
24406044	The knockdown of EZH2 by siRNA induced SN-12 cell senescence, decreased the protein expression level of EZH2, and increased the protein expression of P16
24406044	MiR-138 is a tumor-suppressor miRNA in ccRCC that induces SN-12 cell senescence by downregulating EZH2 expression and upregulating P16 expression
24397850	MSCs were characterized for expression of the genes p16(INK4a) and p21 along with measurements of population doublings (PD), superoxide dismutase (SOD) activity, cellular senescence and differentiation potential
24390753	In vivo, PSC cholangiocytes expressed significantly more senescence-associated p16(INK4a) and gammaH2A
25946838	Peptide AED and EDL increase cell proliferation, decreasing expression of marker of aging p16, p21, p53 and increasing expression of SIRT-6 in young and aged renal cell culture
24344186	Senescence-associated distension of satellites (SADS) occurs earlier and more consistently than heterochromatin foci formation, and SADS is not exclusive to either the p16 or p21 pathways
24335839	The changes of anti-oxidative activities, senescence-related markers senescence-associated beta-galactosidase (SA-beta-gal) and mixed colony-forming unit (CFU-mix), P16(INK4a) and P21(Cip1/Waf1) expression on d 7, and cell cycle were examined on d 1, d 3, and d 7
24335839	Moreover, the irradiation significantly increased SA-beta-gal staining, reduced CFU-mix forming, increased the expression of P16(INK4a) and P21(Cip1/Waf1) in the core positions of the cellular senescence signaling pathways and caused G1 phase arrest of Sca-1(+) HSC/HPCs
24322375	Analysis of expression levels of p53, p21(CIP1), p16(INK4a), p27(KIP1), pRb and E2F1 and genetic knockdown of p21(CIP1) demonstrated an important role of p21(CIP1) in RD-triggered cellular senescence
24302615	The observed antitumor effects of NDRG1 suppression were correlated with activation of major senescence-associated signaling pathways, such as upregulation of tumor suppressors p53, p21 and p16, and decreased phosphorylated Rb
24217920	We show that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (Suz12), thereby activating p16
24217920	Importantly, loss of p16 leads to repression of SA-miRNA expression, intimately coupling this effector of senescence to the SA-miRNA/PcG self-regulatory loop
24165022	YB1 binds to and represses the p16 tumor suppressor gene
24165022	Depletion of YB1 was associated with increased levels of p16 in human and murine primary cells
24165022	Forced expression of YB1 in mouse embryonic fibroblasts resulted in decreased expression of p16 and increased cell proliferation
24165022	Chromatin immunoprecipitation assays showed that YB1 directly associates with the p16 promoter
24165022	Taken together, all our findings indicate that YB1 directly binds to and represses p16 transcription, subsequently resulting in the promotion of cell growth and prevention of cellular senescence
24136988	The molecular balancing act of p16(INK4a) in cancer and aging
24136988	Although it is classically known for its capacity to inhibit cyclin-dependent kinase (CDK) activity, p16(INK4a) is not just a one-trick pony
24136988	Long-term p16(INK4a) expression pushes cells to enter senescence, an irreversible cell-cycle arrest that precludes the growth of would-be cancer cells but also contributes to cellular aging
24136988	Importantly, loss of p16(INK4a) is one of the most frequent events in human tumors and allows precancerous lesions to bypass senescence
24136988	Therefore, precise regulation of p16(INK4a) is essential to tissue homeostasis, maintaining a coordinated balance between tumor suppression and aging
24136988	This review outlines the molecular pathways critical for proper p16(INK4a) regulation and emphasizes the indispensable functions of p16(INK4a) in cancer, aging, and human physiology that make this gene special
24122992	The cells treated with Doxorubicin (0-500 nm) or vehicle control were analyzed for apoptosis, senescence (SA-beta Galactosidase), and expression of CDKN1A (p21), CDKN1B(p27), CDKN2A (p16), E2F1, vimentin and E-cadherin by immuno-histochemistry and/or Western blot
24122992	CONCLUSION: The absence of functional p16, pRB and p53 in DU145 suggests that Id4 could alter additional molecular pathways such as those involving E2F1 to promote senescence and increased sensitivity to doxorubicin-induced apoptosis
24091330	The p16(INK4a) tumor suppressor accumulates in aging tissues, is a biomarker for cellular senescence, and limits stem cell function in vivo
24091330	While the activation of a p53-dependent DDR by dysfunctional telomeres has been well documented in human cells and mouse models, the role for p16(INK4a) in response to telomere dysfunction remains unclear
24091330	Here, we generated protection of telomeres 1b p16-/- mice (Pot1bDelta/Delta;p16-/-) to address the function of p16(INK4a) in the setting of telomere dysfunction in vivo
24091330	We found that deletion of p16(INK4a) accelerated organ impairment and observed functional defects in highly proliferative organs, including the hematopoietic system, small intestine, and testes
24091330	In contrast to p16(INK4a), deletion of p21 did not activate ATR, rescued proliferative defects in Pot1bDelta/Delta hematopoietic cells, and significantly increased organismal lifespan
24091330	Our results provide experimental evidence that p16(INK4a) exerts protective functions in proliferative cells bearing dysfunctional telomeres
24089445	In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16(INK4A)) is deleted
24078830	The results demonstrated that BDMC attenuated oxidative stress-induced senescence-like features which include the induction of an enlarged cellular appearance, higher frequency of senescence-associated beta -galactosidase staining activity, appearance of senescence-associated heterochromatic foci in nuclei, decrease in proliferation capability, and alteration in related molecules such as p16 and retinoblastoma protein
24067365	The cell cycle regulator p16(INK4a) is a key effector upregulated during senescence
24067365	We showed that HLX1 and HOXA9 recruit PRCs to repress INK4a, which constitutes a key mechanism explaining their effects on senescence
24052950	Rapidly expanding clones (RECs) exhibited robust multilineage differentiation and self-renewal potency, whereas the other clones tended to acquire cellular senescence via P16INK4a and exhibited frequent genomic errors
24052415	The expression of p16 and PTEN do not seem to cause synergism of senescence in the benign lesions analyzed in p21p27 double-KO mice
24046371	Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines
24046371	The tumor suppressor p16(INK4A) inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins
24046371	Oncogenic stress induces p16(INK4A) expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor
24046371	Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16(INK4A) activity by mutation or epigenetic silencing
24046371	Human papillomavirus (HPV)-associated tumors express high levels of p16(INK4A) in response to E7 oncoprotein expression
24046371	Induction of p16(INK4A) expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B
24046371	The p16(INK4A) tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival
24046371	This oncogenic p16(INK4A) activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive
24024133	HDFs that undergo replicative senescence display typical morphological features, express senescence-associated beta-galactosidase, and increased levels of the tumor suppressor genes, p16, p21, and caveolin-1
24000115	Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 microM treatments
23997094	Expression of p16(ink4a), a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD(+/+) and MnSOD(+/-) mice
23982736	The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment
23969248	In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-beta-galactosidase staining together with downregulation of E2F target genes
23957394	We also found that vascular smooth muscle cells (SMCs) in the aortic wall of Col1a1(r/r) mice were susceptible to stress-induced senescence, displaying senescence-associated ss-galactosidase (SA-ssGal) activity and upregulated p16(INK4A) in response to angiotensin II infusion
23957394	This revealed that mutant collagen directly reduced replicative lifespan and increased stress-induced SA-ssGal activity, p16(INK4A) expression, and p21(CIP1) expression
23916530	The retinoblastoma protein (RB) and p53 tumor suppressors are central to the process and the growth arrest is primarily implemented by the cyclin-dependent kinase (CDK) inhibitors, p16INK4a and p21CIP1
23904845	No pathogenetic mutations in CDKN2A, BRAF, NRAS, KRAS, cKIT, TP53 and PTEN genes were observed
23897841	Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16(INK4a) (p16), and retinoblastoma (Rb)
23881689	Likewise, p14(Arf), an inducer of cellular senescence, has been associated with the occurrence of T2D
23872946	While DPY30 depletion leads to a reduced level of H3K4me3-marked active chromatin, we observed a concomitant activation of CDK inhibitors, including p16INK4a, independent of H3K4me3
23872946	Because ID proteins are negative regulators of the transcription factors ETS1/2, depletion of DPY30 leads to the transcriptional activation of p16INK4a by ETS1/2 and thus to a senescent-like phenotype
23870914	Twenty-four hour treatment with debarked stems extract resulted in the strong induction of p53 and p16, whereas both leaf extracts inhibited the activation of ERK
23826727	PTEN controls beta-cell regeneration in aged mice by regulating cell cycle inhibitor p16ink4a
23826727	Using several animal and cell models where we can manipulate PTEN expression, we found that PTEN blocks cell cycle re-entry through a novel pathway leading to an increase in p16(ink4a), a cell cycle inhibitor characterized for its role in cellular senescence/aging
23826727	A downregulation in p16(ink4a) occurs when PTEN is lost as a result of cyclin D1 induction and the activation of E2F transcription factors
23826727	The activation of E2F transcriptional factors leads to methylation of p16(ink4a) promoter, an event that is mediated by the upregulation of polycomb protein, Ezh2
23765615	The results reveal an absence of altered DPSC morphology and phenotype following the exogenous introduction of the hTERT gene, which is coupled with a significant reduction in p16 mRNA expression
23758730	TLBZT also induced cell senescence in CT26 colon carcinoma, with concomitant upregulation of p16 and p21 and downregulation of RB phosphorylation
23751258	The study aimed to assess biological ageing in South African HIV-infected adults and HIV-seronegative individuals using two validated biomarkers, telomere length and CDKN2A expression (a mediator of cellular senescence)
23751258	Biological ageing was evaluated by measurement of telomere length and CDKN2A expression in peripheral blood leukocytes
23751258	CONCLUSION: Telomere length and CDKN2A expression were both consistent with increased biological ageing in HIV-infected individuals
23744621	Western blot analysis and confocal-laser scanning microscopy revealed that stachydrine also blocked the high-glucose induced upregulation of p16(INK4A) and downregulation of SIRT1 expression and enzyme activity
23710306	Senescence is activated through an interaction between the p16 and p53 tumor-suppressor genes
23691139	Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A
23676215	INK4a/ARF limits the expansion of cells suffering from replication stress
23676215	In addition, we show that a persistent exposure to RS leads to increased levels of INK4a/Arf products, revealing that INK4a/ARF behaves as a bona fide RS checkpoint
23676215	Our data reveal an unknown role for INK4a/ARF in limiting the expansion of cells suffering from persistent replication stress, linking this well-known tumor suppressor to the maintenance of genomic integrity
23657974	Moreover, the senescence- associated cyclin-dependent kinase inhibitors p16(Ink4A) and p21(Cip1) were induced correlating with activation of the G1/S cell cycle inhibitor retinoblastoma protein and terminal proliferation arrest
23645774	P14ARF is down-regulated during tumour progression and predicts the clinical outcome in human breast cancer
23645774	There was no significant relationship between p16 levels and clinicopathological parameters
23645206	ZNF313 ubiquitinates p21(WAF1) and also destabilizes p27(KIP1) and p57(KIP2), three members of the CDK-interacting protein (CIP)/kinase inhibitor protein (KIP) family of cyclin-dependent kinase inhibitors, whereas it does not affect the stability of the inhibitor of CDK (INK4) family members, such as p16(INK4A) and p15(INK4B)
23644284	Transgenic Thy1-GFP rats and qRT-PCR demonstrated that failure of the regenerating axonal front in ANAs was associated with increased levels of senescence related markers in the graft (senescence associated beta-galactosidase, p16(INK4A), and IL6)
23643076	The expressions of senescence-associated genes p16(INK4a);, p19(Arf);, p53, p21(Cip1/Waf1); mRNA were detected by RT-PCR
23643076	Western blotting was performed to analyze the expressions of p16(INK4a); and p21(Cip1/Waf1); proteins
23623979	Expression of the senescence markers p21(CIP1/WAF1) and p16(INK4a), and SA-beta-galactosidase activity, were higher in HtrA1+/- MEFs than in HtrA1-/- MEFs
23576552	In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53-dependent
23557734	METHODS: Senescence was assessed by measuring the SA-beta-Galactosidase activity, the expressions of p16(INK4a) and ATM, and cell cycle analysis
23557329	RESULTS: We observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways
23516461	Culturing on Wharton's jelly extract delays mesenchymal stem cell senescence through p53 and p16INK4a/pRb pathways
23516461	Reactive oxygen species (ROS), p53, and p16INK4a/pRb expression increased with passaging
23516461	Analysis at the molecular level revealed that WJE-based culture efficiently suppressed the enhancement of intracellular ROS, p53, and p16INK4a/pRb in MSCs
23504375	Late passage fibroblasts had enlarged cell bodies and were more often positive for myofibroblast marker alpha-smooth muscle actin, senescence associated beta-galactosidase and p16 compared with early passage fibroblasts
23494737	As a consequence, SIRT3 antagonized cellular senescence with the characteristic features of delayed SA-beta-gal staining, senescence-associated heterochromatin foci (SAHF) formation, and p16(INK4A) expression
23472054	ING1a overexpression inhibits growth; induces a large flattened cell morphology and the expression of senescence-associated beta-galactosidase; increases Rb, p16, and cyclin D1 levels; and results in the accumulation of senescence-associated heterochromatic foci
23472054	Overexpression of ITSN2 independently induces expression of the p16 and p57(KIP2) cyclin-dependent kinase inhibitors, which act to block Rb inactivation, acting as downstream effectors of ING1a
23468063	Following pretreatment with subcytotoxic concentrations of copper sulfate, U87-MG tumor cells showed typical aging characteristics, including reduced cell proliferation, cell enlargement, increased level of senescence-associated beta-galactosidase (SA beta-gal) activity, and overexpression of several senescence-associated genes, p16, p21, transforming growth factor beta-1 (TGF-beta1), insulin growth factor binding protein 3 (IGFBP3) and apolipoprotein J (ApoJ)
23460854	CDKN2A expression (a cell senescence mediator) was measured in peripheral blood leukocytes and 8-hydroxy-2'-deoxyguanosine (8-OHDG; an oxidative DNA damage marker) levels were measured in plasma
23460854	In participants on ART with undetectable viral load, CDKN2A expression and 8-OHDG levels were higher in those with accelerated aging, as reflected by lower ECD
23454889	How to measure RNA expression in rare senescent cells expressing any specific protein such as p16Ink4a
23451179	Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a), p21 and phosphorylated p53 (Ser15)
23443045	FOXA1 mediates p16(INK4a) activation during cellular senescence
23443045	Mechanisms governing the transcription of p16(INK4a), one of the master regulators of cellular senescence, have been extensively studied
23443045	Here, we report that Forkhead box A1 protein (FOXA1) is significantly upregulated in both replicative and oncogene-induced senescence, and in turn activates transcription of p16(INK4a) through multiple mechanisms
23443045	In addition to acting as a classic sequence-specific transcriptional activator, FOXA1 binding leads to a decrease in nucleosome density at the p16(INK4a) promoter in senescent fibroblasts
23443045	Moreover, FOXA1, itself a direct target of Polycomb-mediated repression, antagonizes Polycomb function at the p16(INK4a) locus
23443045	Finally, a systematic survey of putative FOXA1 binding sites in the p16(INK4a) genomic region revealed an approximately 150 kb distal element that could loop back to the promoter and potentiate p16(INK4a) expression
23443045	Overall, our findings establish several mechanisms by which FOXA1 controls p16(INK4a) expression during cellular senescence
23438604	Consistently, knockdown of pRB, p21(CIP1), and p16(INK4a), but not p53, suppressed SAHF formation induced by BRG1
23434069	Pathological alterations can be perceived by aberrant chromatin sensors, such as the INK4/ARF locus, which initiate tumor suppressive cell senescence programs, and can often result in epithelial stem cell exhaustion
23430755	By double labeling of senescent cells, first by SA-beta-Gal and then by antibodies against genes related to cellular senescence, we found that p21, p16, and RARbeta, but not p53, were upregulated by bexarotene in mammary tumors and in breast cancer cell lines, suggesting involvement of multiple signaling pathways in mediating the senescence program of rexinoids
23423975	Dynamics of senescent cell formation and retention revealed by p14ARF induction in the epidermis
23423975	To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14(ARF) (human ortholog of murine p19(ARF)), a central activator of senescence
23423975	Induction of p14(ARF) in the epidermis rapidly led to widespread apoptosis and cell-cycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence
23423975	The endogenous Cdkn2a products p19(ARF) and p16(Ink4a) were activated by the transgenic p14(ARF) through p53, revealing a senescence-promoting feed-forward loop
23423975	Commitment of cells to senescence required continued p14(ARF) expression, indicating that entry into this state depends on a persistent signal
23423975	Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14(ARF) induction, but irreversibly lost their ability to proliferate and initiate follicle growth
23423975	Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14(ARF) induction
23408353	Emerging evidence suggests that oncogene-induced senescence requires transcriptional induction of the CDKN2A gene locus as well as comprehensive chromatin modifications involved in epigenetic silencing of pro-proliferative genes
23408353	Moreover, recent work in pancreatic cancer mouse models proposes that inactivation of the CDKN2A tumour suppressor locus is the molecular switch required for senescence evasion and unleashed K-Ras driven malignant transformation in the pancreas
23359450	Most of the MSCs cultured under normoxic conditions ceased to proliferate after 20-28 PD, while few senescent cells were found in the hypoxic, PEDF-hypoxic and PEDF-normoxic cultures; this was associated with downregulation of p53 and p16 expression and decreased oxidative stress
23358854	In this study, fibroblasts from GU-OSCC were senescent relative to fibroblasts from GS-OSCC, epithelial dysplastic tissues or normal oral mucosa, as demonstrated by increased senescence-associated beta-galactosidase (SA beta-Gal) activity and overexpression of p16(INK4A)
23332765	Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker
23332765	Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death
23332765	Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells
23332765	This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation
23324396	Using a high-content siRNA screening assay for cell morphology and proliferation measures, we identify 12 senescence-regulating kinases and determine their senescence marker signatures, including elevation of senescence-associated beta-galactosidase, DNA damage and p53 or p16 (INK4a) expression
23318426	Restored expression of the cyclin-dependent kinase inhibitor p16INK4a abrogated the CSC properties of iCSCL-10A cells, by inducing cellular senescence
23316069	We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4)
23316069	Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity
23316069	NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells
23296673	In addition to an obligatory proliferation arrest, senescent cells manifest various senescence markers: mTOR-mediated hypertrophic growth (cell size increase), cell flattening, senescence-associated beta galactosidase (SA-beta gal) staining, expression of negative cell cycle regulators p53, p21(Waf1) and p16(Ink4a), specific chromatin reorganization including DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), senescence-associated secretory phenotype (SASP) and other features
23296652	Concurrent immunocytochemical analysis of expression of p21(WAF1), p16(INK4a), or p27(KIP1) cyclin kinase inhibitors provides additional markers of senescence
23257424	The potential effect of CTX on senescence of bone marrow hematopoietic cells was analyzed by detecting p16(Ink4a) mRNA relative expression and SA-beta-galactosidase (gal) staining
23257424	Furthermore, the serial-transplantation model showed that these mice received transplantation of bone marrow hematopoietic cells from CTX-treated mice exhibited a high expression of p16(Ink4a) mRNA and SA-beta-gal staining
23253087	As p16 expression occurs in nevi but falls with progression toward melanoma, we here investigated whether p53-dependent senescence occurs at some stage and, if not, what defects were detectable in this pathway, using immunohistochemistry
23249948	HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence
23234142	The expressions of senescence-related genes such as p16, p53, p21, Rb, were detected by RT-PCR and the changes in ultramicro-morphology were observed by transmission electron microscopy
23216904	Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including beta-galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16Ink4a
23216904	This suggests that Nox-generated ROS transduce senescence signals by activating the p53 and p16Ink4a pathway
23187803	For example, induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR, which, in turn, converts p21/p16-induced arrest into senescence (geroconversion)
23185405	METHODOLOGY: To address this issue we have measured in the blood leucocytes of MDD patients (N=17) and controls (N=16) the expression of two genes identified as robust biomarkers of human aging and telomere dysfunction: p16(INK4a) and STMN1
23185405	RESULTS: The OGG1, p16(INK4a), and STMN1 gene were significantly up-regulated (25 to 100%) in the leucocytes of MDD patients
23185405	Expression of p16(INK4a) and STMN1 was directly correlated with anxiety scores in the depression group, and that of p16(INK4a), STMN and TERT with the depression and anxiety scores in the combined sample (MDD plus controls)
23185405	CONCLUSIONS: Expression of p16(INK4) and STMN1 is a promising biomarker for future epidemiological assessment of the somatic impact of depressive and anxious symptoms, at both clinical and subclinical level in both depressive patients and general population
23132454	Tissue microarray analysis of cyclin-dependent kinase inhibitors p21 and p16 in Fuchs dystrophy
23132454	PURPOSE: To investigate the novel application of tissue microarray (TMA) technology to corneal disease and to report altered protein expression of senescence-associated cyclin-dependent kinase inhibitors p21 and p16 in Fuchs endothelial corneal dystrophy (FECD)
23132454	TMA sections were immunolabeled for p21 and p16 and analyzed using a 9-grade scoring system (0-8)
23132454	Corneal endothelial p21 and p16 expression levels in FECD specimens compared with controls served as main outcome measures
23132454	Immunolabeling of whole tissue sections showed statistically significant endothelial overexpression of both proteins (p21 and p16, P < 0
23132454	It demonstrates p21 and p16 overexpression in the corneal endothelium of genetically undifferentiated FECD patients supporting a role of cellular senescence in the pathogenesis of FECD
23130145	MPs increased expression of cell cycle proteins p 21 cip1 and p16ink4a and stimulated phosphorylation of p66(Shc) in ECs (P<0
23124852	After scavenging ROS with N-acetylcysteine, Wnt/beta-catenin signaling-induced MSC aging was significantly attenuated and the DNA damage and the expression of p16(INK4A), p53, and p21 were reduced in MSCs
23104211	Acceleration of gastric tumorigenesis through MKRN1-mediated posttranslational regulation of p14ARF
23104211	METHODS: A link between MKRN1 and ARF was examined in MKRN1 null mouse embryonic fibroblasts (MEFs) and in human fibroblasts and gastric cancer cells by silencing MKRN1 using small interfering RNA (siRNA) and short hairpin RNA (shRNA)
23104211	Ubiquitination and proteasomal degradation assays were used to assess p14ARF degradation associated with MKRN1
23104211	MKRN1 and p14ARF expression levels were analyzed with immunohistochemistry in malignant and normal tissues from gastric cancer patients and with chi(2) tests
23104211	The tumor growth of gastric cancer cells stably expressing MKRN1 shRNA, p14ARF shRNA, or both was examined in mouse xenograft models (n = 4-6) and analyzed with unpaired t tests
23104211	Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation
23104211	A statistically significant association was shown between MKRN1 overexpression and p14ARF underexpression (P =
23104211	Xenograft analyses using p53-functional AGS or -dysfunctional SNU601 cells displayed statistically significant tumor growth retardation by silencing MKRN1, which was reversed under depletion of p14ARF (AGS cells, MKRN1 knockdown tumors vs MKRN1 and p14ARF knockdown tumors: 164
23104211	CONCLUSIONS: We demonstrated that MKRN1 functions as a novel E3 ligase of p14ARF and that it potentially regulates cellular senescence and tumorigenesis in gastric cancer
22971926	Knockdown of MDH1 in young HDFs (PD 20) and the IMR90 human fibroblast cell line resulted in the appearance of significant cellular senescence features, including senescence-associated beta-galactosidase staining, flattened and enlarged morphology, increased population doubling time, and elevated p16(INK4A) and p21(CIP1) protein levels
22969849	LYTF also induces cell senescence, as indicated by a large and flattened morphology, senescence-activated beta-galactosidase-positive staining and G0/G1 cell cycle arrest, accompanied by the up-regulation of p16 and p21 and the down-regulation of retinoblastoma protein phosphorylation
22955272	In contrast, ARF and p27(KIP1), which are also E2F1 targets, are not repressed by Rb and heterochromatin formation
22955272	By comparing the promoter sequences of these genes, we found a novel TAAC element that is present in the cellular senescence-inhibited gene, proliferating cell nuclear antigen, and CCNA2 promoters but absent from the ARF and p27(KIP1) promoters
22933405	As p16(INK4a) protein expression was not significantly modified, and based on our previous data, we propose that resveratrol does not affect fibroblast replicative senescence, but improves tissue maintenance and repair during normal cellular aging
22915839	Sustained p16(INK4a) and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence
22897574	At 48 h post-transfection, the protein expression of p16 in PON1 siRNA-treated HDMECs was higher than that in scrambled siRNA-treated HDMECs
22888763	These peaks mapped to the Major Histocompatibility (MHC) locus on 6p21 and the INK4/ARF (CDKN2a/b) tumor suppressor locus on 9p21
22859216	The defects in immune networks resulted in suppressed p21- and p16/pRb-dependent senescence, which caused an increase in proliferation and a decrease in apoptotic and autophagy-associated cell death in mouse livers
22855034	At the end of the 48-h culture, the following analyses were performed including determination of senescence-associated beta-galactosidase (SAbeta-Gal) activity, flow cytometry analysis of cell cycle, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses of p16, Cyclin D1, cyclin-dependent kinase 4 (CDK4) and retinoblastoma (Rb) mRNA expression, and Western blotting analyses of p16, cyclin D1, CDK4 and phosphoretinoblastoma (pRb) protein expressions
22855034	Compared with the old group, VSMCs in the treated groups had a significant increase in p16 and Rb mRNA expression and a significant decrease in Cyclin D1 and CDK4 mRNA expression (P<0
22855034	Compared with the old group, VSMCs in the treated groups had a significant increase in p16 protein expression and a significant decrease in cyclinD1, CDK4 and pRb protein expressions (P<0
22820504	The expression of p16(INK4A) was significantly increased, whereas levels of CDK4, CDK6 and p-Rb expression were decreased in the MSCs from both untreated and treated SLE patients
22820504	Knockdown of p16(INK4A) expression reversed the senescent features of MSCs and upregulated TGF-beta expression
22820504	Further, we have found that p16(INK4A) promotes MSC senescence via the suppression of the extracellular signal regulated kinase (ERK) pathway
22820504	Our results demonstrated that MSCs from SLE patients were senescent and that p16 (INK4A) plays an essential role in the process by inhibiting ERK1/2 activation
22797186	Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16(INK4a) expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal
22797186	Here, loss of the INK4a locus in mice, which allows escape from p16(INK4a)-dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival
22797186	Compared with wild-type controls, kidneys from INK4a(-/-) mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury
22797186	Consistently, mice that received kidney transplants from INK4a/ARF(-/-) donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes
22791394	Here, we report an important role for c-Abl in replicative senescence and immortalization by regulating the expression of two tumor suppressors that induce cellular senescence, p53 and p16(INK4a)
22791394	This resistance was attributed to premature senescence and reduced survival in senescent c-Abl (-/-) cells due to an increase in p16(INK4a) and p53 expression
22783442	This event could be due to the loss of senescence pathway effectors, including p16 (INK4a)-pRb or ARF-p53
22772724	Stromal p16 expression differentiates endometrial polyp from endometrial hyperplasia
22772724	In this study, we examined p16 expression in 35 endometrial polyps and 33 cases of endometrial hyperplasia that included 16 simple hyperplasias, 14 complex atypical hyperplasias, and 3 complex hyperplasias without atypia
22772724	Stromal p16 expression differed significantly between the two groups; it was seen in 31 (89 %) endometrial polyps, but in only 1 (3 %) endometrial hyperplasia
22772724	Six cases of endometrial hyperplasia within an endometrial polyp were also examined and all cases showed stromal p16 expression
22772724	There was no difference in glandular p16 expression between endometrial polyps 33 (94 %) and hyperplasia 27 (82 %)
22772724	Stromal p16 expression might be a peculiar characteristic of endometrial polyp and constitute a useful marker for the diagnosis, especially in fragmented specimens from biopsy or curettage
22772724	Stromal p16 expression might be a reflection of p16-induced cellular senescence, which has been documented in several benign mesenchymal neoplasms
22754337	Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction
22754337	Previous studies have shown that p16(Ink4a) plays an important role in the response to DNA damage signals caused by telomere dysfunction
22754337	In this study, we crossed Wrn(-/-) and p16(Ink4a-/-) mice to knock out the p16(Ink4a) function in a Wrn null background
22754337	Growth curves showed that loss of p16(Ink4a) could rescue the growth barriers that are observed in Wrn(-/-) mouse embryonic fibroblasts (MEFs)
22754337	By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16(Ink4a) did not dramatically affect the global DNA damage response of Wrn(-/-) MEFs induced by doxorubicin
22754337	However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2(DeltaBDeltaM), loss of p16(Ink4a) could partially overcome the DNA damage response by disabling p16(Ink4a) up-regulation and reducing the accumulation of gamma-H2AX that is observed in Wrn(-/-) MEFs
22754337	In contrast, p16(Ink4a-/-) and p16(Ink4a-/-)Wrn(-/-) MEFs could continuously grow and lose expression of the exogenous TRF2(DeltaBDeltaM) in their late passages
22754337	In summary, our data suggest that in the context of telomere dysfunction, loss of p16(Ink4a) function could prevent cells from senescence
22754337	These results shed light on the anti-aging strategy through regulation of p16(Ink4a) expression
22738669	Expression of p16(INK4a) as a biomarker of T-cell aging in HIV-infected patients prior to and during antiretroviral therapy
22738669	The p16(INK4a) tumor suppressor gene is a mediator of cellular senescence and has been suggested to be a biomarker of 'molecular' age in several tissues including T cells
22738669	To determine the association of both active and suppressed HIV infection with T-cell aging, T-cell p16(INK4a) expression was compared between 60 HIV+ suppressed subjects, 23 HIV+ untreated subjects, and 18 contemporaneously collected HIV-negative controls, as well as 148 HIV-negative historical samples
22738669	In patients on cART with suppressed viral loads, however, p16(INK4a) levels were similar to uninfected controls and correlated with chronologic age, with a trend toward an inverse correlation with CD4 count
22738669	These data show that p16(INK4a) is a reliable biomarker of T-cell aging in HIV+ patients with suppressed viral loads and suggest that poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16(INK4a), a marker of cellular senescence
22689861	B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16
22633096	Cellular senescence was evaluated by senescence-associated beta-galactosidase (SA-beta-gal) staining and an immunohistochemical analysis of p21 and p16 protein expression
22633096	SA-beta-gal staining and the expression of p16 and p21 were increased significantly in renal biopsy specimens obtained from grades I-II IgAN patients compared with controls (P < 0
22633096	A correlation analysis showed that the expressions of p16, p21, and SA-beta-gal staining were associated significantly with blood pressure and renal function (P < 0
22612594	Here, we studied whether younger biological age is related to fewer senescent cells in middle-aged individuals with the propensity for longevity, using p16INK4a as a marker for cellular senescence
22606351	Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence
22606351	Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways
22606351	CONCLUSIONS/SIGNIFICANCE: This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation
22555846	IS increased the mRNA expression of p53 and p21 in HASMCs, whereas it did not change that of p16 and retinoblastoma protein (pRb)
22555620	This was accompanied by increases in expression and activity of the senescence marker collagenase and expression of p16/p21 in bone
22555620	Finally, we demonstrated that bone cell senescence is associated with decreased Sirt1 expression and activated p53, p16, and p21
22531458	Total disc proteoglycan (PG) content [1,9-dimethylmethylene blue (DMMB) assay], aggrecan proteolysis (immunobloting analysis), and cellular senescence (p16INK4a immunohistochemistry) were analyzed
22521293	ETS-dependent p16INK4a and p21waf1/cip1 gene expression upon endothelin-1 stimulation in malignant versus and non-malignant proximal tubule cells
22521293	AIM: Cellular senescence, leading to cell death through prevention of regular cell renewal, is associated with the upregulation of the tumor suppressor gene p16(INK4a)
22521293	While this mechanism has been described as leading to progressive nephron loss, p16(INK4a) upregulation in renal cell carcinoma has been linked to a disease-specific improved patient survival rate
22521293	While in both conditions endothelin-1 is also upregulated, the signaling pathway connecting ET-1 to p16(INK4a) has not been characterized until this study
22521293	KEY FINDINGS: In malignant renal proximal tumor cells (Caki-1), an activation of p16(INK4a) and p21(waf1/cip1) was observed
22521293	This indicates that other ETS members may be involved in the observed p16(INK4a) upregulation (as described in the literature)
22521293	SIGNIFICANCE: ETS1, ERK2 and Mxi2 are important complex partners initiating increased p16(INK4a) and p21w(af1/cip1) activation in renal tumor cells
22513787	Specifically, we analyzed effectors of senescence, including p16(INK4a), p53, and DNA damage (gamma-H2AX), as well as predictive markers of senescence including Ki67, PML, senescence-associated beta-galactosidase, heterochromatic foci (H3K9Me, 4'-6-diamidino-2-phenylindole), and nuclear size
22509111	High expression of p16INK4a and low expression of Bmi1 are associated with endothelial cellular senescence in the human cornea
22509111	PURPOSE: Determine cyclin-dependent kinase inhibitor 2A (p16(Ink4a)) and polycomb ring finger oncogene (Bmi1) expression in corneal endothelium samples from different age groups and test whether the expression of p16(INK4a) and Bmi1 are associated with endothelial cellular senescence in human cornea
22509111	The expression of p16(INK4a) and Bmil were analyzed by real-time PCR, immunohistochemistry, and immunofluorescence
22509111	RESULTS: Through real-time PCR, we detected less than threefold decreases in Bmi1 expression and greater than fivefold increases in p16(INK4a) expression associated with aging
22509111	Our immunohistochemistry experiments showed that the expression of p16(INK4a) in older donors was stronger than that in younger donors and the expression of Bmi1 in older donors was weaker than that in younger donors
22509111	Results from both the immunohistochemistry and real-time PCR experiments confirmed increased expression of p16(INK4a) and decreased expression of Bmi1 with age in HCECs
22509111	Additionally, the results of immunofluorescence double-staining for p16(INK4a) and Bmi1 further validated the immunocytochemistry and real-time PCR results
22509111	CONCLUSIONS: Our data are the first to demonstrate that high expression of p16(INK4a) and low expression of Bmi1 are associated with endothelial cellular senescence in human cornea
22480653	Notably, several tumour suppressors, such as p53, pRb or p16(Ink4a), play key roles both in the initiation of the senescence program and in its maintenance, which often involves epigenetic changes
22467239	We first observed that AGR2 was overexpressed in Chinese Han PCa tissues and had a positive correlation with cyclin D1 and p-Rb but not with p16(INK4a)
22424056	Induction of senescence in hMSC-TERT was demonstrated by a variety of markers, including characteristic cell morphology and enlargement, vacuolisation, multinucleation, induction of senescence associated beta-galactosidase, cell cycle arrest, and increased levels of a cell cycle inhibitor p16
22363855	The primary mediator of senescence in nevi appears to be p16
22359668	Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling
22355043	Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes
22340434	Quantitative assessment of higher-order chromatin structure of the INK4/ARF locus in human senescent cells
22340434	The INK4/ARF locus encodes p15(INK4b) , ARF, and p16(INK4a) genes in human chromosome 9p21, the products of which are known as common key reprogramming regulators
22340434	Compared with growing fibroblasts, the CCCTC-binding factor CTCF is remarkably up-regulated in iPS cells with silencing of the three genes in the locus and is reversely down-regulated in OIS cells with high expression of p15(INK4b) and p16(INK4a) genes
22340434	There are at least three CTCF-enriched sites in the INK4/ARF locus, which possess chromatin loop-forming activities
22340434	These CTCF-enriched sites and the p16(INK4a) promoter associate to form compact chromatin loops in growing fibroblasts, while CTCF depletion disrupts the loop structure
22340434	In addition, the INK4/ARF locus has an intermediate type of chromatin compaction in iPS cells
22340434	These results suggest that senescent cells have distinct higher-order chromatin signature in the INK4/ARF locus
22333593	However, senescence induction by endogenous p16 was delayed in primary normal human mammary epithelial cells with reduced pRb but not with reduced p107 or p130
22326283	Hepatitis C virus Core protein overcomes stress-induced premature senescence by down-regulating p16 expression via DNA methylation
22326283	For this effect, Core down-regulated levels of p16 via promoter hypermethylation and subsequently induced phosphorylation of Rb in the presence of H2O2
22326283	The potentials of Core to inactivate Rb and suppress H2O2-mediated cellular senescence were abolished when levels of p16 were recovered by either exogenous complementation or inhibition of DNA methylation
22301954	Immunohistochemical and global gene expression analysis of overt Emu-Myc Wrn(Deltahel/Deltahel) lymphomas showed a marked increase in expression of the CDK inhibitor, p16(Ink4a), as well as elevation of TAp63, a known mediator of senescence
22285491	RUVBL2 is a novel repressor of ARF transcription
22285491	ARF is the second most commonly inactivated tumor suppressor behind p53
22285491	However, the detailed mechanism underlying the transcriptional control of ARF remains largely unknown
22285491	Here we report RUVBL2 as a novel transcriptional repressor of ARF
22285491	Ectopic expression of RUVBL2 decreases the levels of ARF, whereas knockdown of RUVBL2 results in a marked increase in ARF levels
22285491	Mechanistically, RUVBL2 binds to the distal region of ARF promoter, thus leading to the repression of ARF transcription
22267761	The lung tissue in which type II cells contained higher numbers of gammaH2AX foci per cell had higher percentages of type II cells that expressed p16(INK4a) (p16), phosphorylated nuclear factor (NF)-kappaB and interleukin (IL)-6, and of alveolar wall cells that expressed active caspase-3
22267761	The type II cells that contained higher numbers of gammaH2AX foci per cell had higher rates of expression of p16, phosphorylated NF-kappaB, and IL-6
22265741	The expression of genes related to senescence such as CHEK1 and cyclin-dependent kinase inhibitor p16(ink4a) was increased with age, however genes of apoptosis were downregulated
22258036	Consistent with these findings, the protein levels of both p16 and cyclin E, which are known to induce cellular senescence and promote proliferation, respectively, were increased in BPA-exposed HMEC
22258036	Furthermore, DNA methylation levels of genes related to development of most or all tumor types, such as BRCA1, CCNA1, CDKN2A (p16), THBS1, TNFRSF10C and TNFRSF10D, were increased in BPA-exposed HMEC
22242193	1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression
22233735	METHODS: We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14Arf and used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis
22233735	RESULTS: An in depth analysis of 52 fibroids along with matching myometrium from 31 patients revealed in almost all cases a higher expression of p14Arf in the tumors than in the matching normal tissue
22233735	Because as a rule fibroids express much higher levels of p14Arf, a major negative regulator of MDM2, than matching myometrium it was then analyzed if fibroids are more sensitive against nutlin-3 treatment than matching myometrium
22206000	Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells
22206000	The cyclin dependent kinase inhibitors p21(CIP1/WAF1) and p16(INK4a) govern the G(1)/S cell cycle checkpoint and are essential for determining whether a cell enters into an arrested state
22206000	The homeodomain transcription factor MEOX2 is an important regulator of vascular cell proliferation and is a direct transcriptional activator of both p21(CIP1/WAF1) and p16(INK4a)
22206000	We compared the ability of MEOX1 and MEOX2 to activate p21(CIP1/WAF1) and p16(INK4a) expression and induce endothelial cell cycle arrest
22206000	Our results demonstrate for the first time that MEOX1 regulates the MEOX2 target genes p21(CIP1/WAF1) and p16(INK4a)
22206000	MEOX1 and MEOX2 activate p16(INK4a) in a DNA binding dependent manner, whereas they induce p21(CIP1/WAF1) in a DNA binding independent manner
22200425	Administration of indoxyl sulfate to hypertensive rats reduces renal expression of Klotho and promotes cell senescence, with expression of senescence-associated beta-galactosidase, p53, p21, p16, and retinoblastoma protein, accompanied by kidney fibrosis
22200425	It promotes cell senescence, with expression of senescence-associated beta-galactosidase, p53, p21, p16, and retinoblastoma protein, in the aorta of hypertensive rats
22194422	Gene analysis demonstrated a significant increase of both the amount and the transcription rates of p16(INK4a) and p21(Cip1) mRNA in OP rats
22194422	The increased p16(INK4a) and p21(Cip1) also caused a significant decrease in the level of phosphorylation of retinoblastoma protein
22194422	In OP rats, the increase of p16(INK4a) was associated with the higher acetylation levels of histone H4 at the p16(INK4a) promoter and coding region and lower methylation level of histone H3 lysine-27 in the p16(INK4a) coding region
22182507	On the other hand, two cyclin-dependent kinase inhibitors, p16INK4a and p14ARF, are effective inhibitors of NF-kappaB signaling
22170163	IMR90 cells showed typical features of senescent cells, like senescence-associated (SA) beta galactosidase expression, including up-regulation of p53 and p14ARF proteins and of p21(waf1) as well, but not of p16(INK4A) cyclin-dependent kinase (Cdk) inhibitor
22113172	AngII with high salt did not change the expression of p16, another CDK inhibitor
22102693	In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclin-dependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF
22102693	Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence
22102004	The expression of p16 and p21, considered as markers for in vitro senescence, was higher in CD28+ CD57+ cells than in other subpopulations in both age groups
22102004	The expression of p21 was age-related, which was not the case for p16
22102004	Thus, although both p16 and p21 are involved in T-cell senescence, they appear to behave differently
22102004	Their higher levels of p16 and p21 expression, coupled with their higher prevalence in the elderly participants make CD28+ CD57+ cells the subpopulation of T-cells most closely corresponding to the concept of senescent cells
22100412	Furthermore, we found that Jhdm1b accelerates cell cycle progression and suppresses cell senescence during reprogramming by repressing the Ink4/Arf locus
22095030	In addition, ING proteins are thought to interact with and modulate the function of auxiliary members of p53 pathway, such as MDM2, ARF , p300, and p21, indicating their widespread involvement in the regulation and function of this prominent tumor suppressor pathway
22067611	Oncoprotein expression was seen in both groups except for a noted absence of p16 in the tDPSCs
22067611	Also examined were the expression of genes involved in proliferation and mineralization such as human alkaline phosphatase (ALP), beta-actin, collagen 1 (col-1), core binding factor (cbfa-1), dentin matrix protein (DMP-1), dentin sialophosphoprotein (DSPP), GAPDH, hTERT, osteocalcin (OCN), osteopontin (OPN) as well as oncoproteins involved in senescence (p16, p21 and p53) using RT-PCR
22067611	CONCLUSIONS: These results indicate maintainance of odontoblast-like differentiation characteristics after retroviral transformation with hTERT and suggest a possible link with a reduced p16 expression
22052190	Cellular senescence induced by PATZ1 knockdown in young cells was rescued by knockdown of p53, but not by knockdown of p16(INK4a)
22048312	To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug
22048312	In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes
22038097	In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1
22037549	Compared with early-passage HAEC, late-passage HAEC had a reduced proliferation rate and increased staining for senescence-associated beta-galactosidase and the tumor suppressor p16(INK4a)
22037160	Oncogenic stress induces at least three intrinsic pathways, p16/pRb-, Arf/p53/p21- and the DNA damage response (DDR)-pathways, that induce premature senescence if the stress exceeds a threshold level
22032700	The effects of high glucose and Tanshinone IIA on cellular senescence of HPMC were examined by observing cell generation, growth rate, cell cycle, positive rate of senescence-associated beta-galactosidase (SA-beta-gal) staining, telomere length, and expression of p16 and p21
22032700	The positive rate of SA-beta-gal staining was increased; the telomere length was shortened; and the expressions of p16 and p21 were increased
22032700	Tanshinone IIA may delay the process of senescence of HPMC induced by high glucose by increasing cell generations and growth rate, decreasing the rate of G1 phase and the positive rate of SA-beta-gal staining, lengthening the telomere, and decreasing the expression of p16 and p21
22025288	Cellular senescence and tumor suppressor gene p16
22025288	While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control
22025288	Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors
22025288	PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression
22025288	Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16
22020331	Here, we present evidence that loss of BTG3 in normal cells induced cellular senescence, which was correlated with enhanced ERK-AP1 signaling and elevated expression of the histone H3K27me3 demethylase JMJD3/KDM6B, leading to acute induction of p16(INK4a)
22019631	In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS)
22014293	The activation was associated with a significant reduction in hematopoietic cell clonogenic function, an increased expression of p16(INK4a) (p16), and an elevated senescence-associated beta-galactosidase (SA-beta-gal) activity
22010578	Cellular senescence is an irreversible cell cycle arrest triggered by the activation of oncogenes or mitogenic signaling as well as the enforced expression of tumor suppressors such as p53, p16(INK4A) and promyelocytic leukemia protein (PML) in normal cells
22010578	The cellular levels of p16(INK4A) and p53 are elevated during premature senescence induced by depletion of E2FBP1, and the depletion of p16(INK4A), but not p53 rescued senescent cells from growth arrest
22010578	Similar to human normal fibroblasts, the growth inhibition induced by E2FBP1 depletion is also observed in human tumor cells with intact p16(INK4A) and Rb
25961265	The mRNA level of the cell cycle inhibitor p16 remains unchanged whereas that of the tumor suppressor p21 is strongly up-regulated
21933340	Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence
21933340	Furthermore, we found that Id1 is the mediator through which Smurf2 regulates p16 expression, providing a mechanistic link between Smurf2 and p16 expression during senescence
21909125	H2O2 (100 mumol/L) significantly decreased Sirt1 expression, and induced up-regulation of p53 acetylation and p16(INK4a), which were blocked by pre-treatment with RHL (10 mumol/L)
21909125	CONCLUSION: RHL protected HUVECs against cellular senescence induced by H2O2, via up-regulation of Sirt1 expression and down-regulation of the expression of acetyl-p53 and p16(INK4a)
21896275	The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence
21896275	Here we studied the functions of ING1 isoforms in cellular senescence and gene regulation, with focus on p16(INK4a)
21896275	Overexpression of p33(ING1b) induces cellular senescence and upregulates p16(INK4a) expression in 2BS fibroblasts
21880712	Senescent cells often express p16(INK4a), a cyclin-dependent kinase inhibitor, tumor suppressor, and biomarker of aging, which renders the senescence growth arrest irreversible
21880712	Here, we show that ectopic expression of p16(INK4a) and another cyclin-dependent kinase inhibitor, p21(CIP1/WAF1), induces senescence without a SASP, even though they induced other features of senescence, including a stable growth arrest
21880712	Additionally, human fibroblasts induced to senesce by ionizing radiation or oncogenic RAS developed a SASP regardless of whether they expressed p16(INK4a)
21880712	Cells induced to senesce by ectopic p16(INK4a) expression lacked paracrine activity on epithelial cells, consistent with the absence of a functional SASP
21880712	Nonetheless, expression of p16(INK4a) by cells undergoing replicative senescence limited the accumulation of DNA damage and premature cytokine secretion, suggesting an indirect role for p16(INK4a) in suppressing the SASP
21880712	These findings suggest that p16(INK4a)-positive cells may not always harbor a SASP in vivo and, furthermore, that the SASP is not a consequence of p16(INK4a) activation or senescence per se, but rather is a damage response that is separable from the growth arrest
21852385	Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53, where it is associated with an induction of p16
21843507	All-trans retinoic acid induces cellular senescence by up-regulating levels of p16 and p21 via promoter hypomethylation
21843507	All-trans retinoic acid (ATRA) induces cellular senescence via up-regulation of p16 and p21; however, the action mechanism of ATRA is unknown
21843507	Here, we show that ATRA induces promoter hypomethylation of p16 and p21 via down-regulation of DNA methyltransferases 1, 3a, and 3b to facilitate binding of Ets1/2 to the p16 promoter and p53 to the p21 promoter, resulting in up-regulation of their expression and subsequent induction of cellular senescence in HepG2 cells
21764698	OBJECTIVE: To investigate the role of lycium bararum polysaccharides (LBP) on angiotensin II (AngII)-induced senescence of human umbilical vein endothelial cells (HUVECs) and expressions of P53 and P16 and explore the mechanism of LBP against aging
21764698	Western blotting was employed to detect the expression of P53 and P16 in the exposed cells
21764698	The expression levels of P53 and P16 were significantly increased in the cells with AngII exposure (P<0
21764698	LBP treatment also increased the cell viability and significantly decreased the expression levels of P53 and P16 (P<0
21757686	The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation
21736542	The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb, whose expression is controlled by two distinct proteins, p19(Arf) and p16(Ink4a), respectively, which are encoded by the cdkn2a locus
21736542	Oxygen induces the expression of the JDP2 gene and JDP2 then inhibits the recruitment of polycomb repressive complexes (PRCs1 and 2) to the promoter of the gene encoding p16(Ink4a), resulting in the inhibition of methylation of lysine 27 of histone H3
21719760	Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions
21703415	Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression
21671044	Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere
21657082	OBJECTIVE: To investigate the relation between the effect of ginsenoside Rg1 to delay hematopoietic stem cell senescence and the expression of p16(INK4a)
21657082	The expression of senescence associated p16(INK4a) mRNA and p16(INK4a) protein was examined by RT-PCR and western blotting
21657082	RESULT: Compared with aging group, the percentage of positive cells expressed SA-beta-gal and cells in G1 phase decreased and the number of forming colony of mixed hematopoietic progenitor increased and it showed higher expression of p16(INK4a) mRNA and p16(INK4a) protein in Rg1 treat aging group and Rg1 delay aging group
21657082	Furthermore the percentage of positive cells expressed SA-beta-gal, cells in G1 phase, the number of forming colony of mixed hematopoietic progenitor and the expression of p16(INK4a) mRNA and protein decreased in Rg1 delay aging group compared with Rg1 treat aging group
21636552	Immunohistochemistry was used to examine p16(INK4a) levels in pilocytic astrocytoma
21636552	BRAF(V600E)-expressing cells subsequently stopped proliferating and induced markers of oncogene-induced senescence including acidic beta-galactosidase, PAI-1, and p16(INK4a) whereas controls did not
21636552	Immunohistochemical examination of 66 pilocytic astrocytomas revealed p16(INK4a) immunoreactivity in the majority of cases, but patients with tumors negative for p16(INK4a) had significantly shorter overall survival
21636552	Induction of senescence by BRAF may help explain the low-grade pathobiology of pilocytic astrocytoma, whereas worse clinical outcomes associated with tumors lacking p16(INK4a) expression could reflect failure to induce senescence or an escape from oncogene-induced senescence
21619050	Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer
21619050	However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function
21619050	Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structure-function relationship of P16 and for human cancers
21618508	To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab-associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53
21618508	These findings demonstrate a novel antitumor activity of VEGF inhibitors in CRC, involving p16
21616554	Further examination revealed increased expression levels of senescence-associated genes such as p16, p21, p53, and caveolin in these cells along with a reduced proliferation rate
21615674	Genotoxic stress induced by bleomycin and oxidative stress enhanced susceptibility of young mice to pneumonia and was positively correlated with enhanced p16, inflammation, and LR levels
21594579	Novel ARF/p53-independent senescence pathways in cancer repression
21594579	Induction of cellular senescence by oncogenic insults, such as Ras overexpression or by inactivation of PTEN tumor suppressor, triggers an ARF/p53-dependent tumor-suppressive effect which can significantly restrict cancer progression
21594579	Given the important role of the ARF/p53 pathway in cellular senescence and tumor suppression, drugs that stabilize p53 expression have been developed and tested in clinical trials
21594579	However, a major hurdle for p53 targeting in cancer treatment arises from the frequent deficiency or mutation of ARF or p53 in human cancers, which, in turn, profoundly compromises their tumor-suppressive ability
21572997	Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16(INK4A) and p21(CIP1/WAF1) expression
21572997	DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16(INK4A) and p21(CIP1/WAF1) promoter regions
21572997	Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16(INK4A) and p21(CIP1/WAF1) promoter regions
21572997	Taken together, DNMTs have a critical role in regulating the cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16(INK4A) and p21(CIP1/WAF1) promoter regions
21559395	In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16
21559395	In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis
21518927	The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway
21518927	Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer
21518927	A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways
21518927	This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway
21518927	Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a
21518927	Accordingly, human ALCLs showed no expression of either p16INK4a or pRb
21518927	Up-regulation of the histone-demethylase Jmjd3 and de-methylation at the p16INK4a promoter contributed to the effect of NPM-ALK on p16INK4a, which was transcriptionally regulated
21518927	These data demonstrate that p16INK4a/pRb may function as an alternative pathway of oncogene-induced senescence, and suggest that the reactivation of p16INK4a expression might be a novel strategy to restore the senescence program in some tumors
21498692	HMGA2 and p14Arf: major roles in cellular senescence of fibroids and therapeutic implications
21498692	RESULTS: In fibroid cells, expression of HMGA2 decreased with passaging while that of p14(Arf) increased
21498692	This, along with a significant correlation between p14(Arf) and BAX expression in native fibroids, suggests that p14(Arf) triggers senescence as well as apoptosis
21498692	CONCLUSION: p14(Arf) and HMGA2 seem to play a pivotal role in controlling the growth of fibroid cells
21486894	The cellular senescence marker; p16(INK4a) and p21(WAF1/Cip1)-positive bile ductular cells were increased in stages 3 and 4
21456046	The expression of both genes was inversely correlated during senescence in vitro but contrary to the expectations in adipose tissue derived stem cells (ADSCs) stimulation of HMGA2 by FGF1 increased the expression of p14(Arf)
21456046	Based on the assumption that in ADSCs p14(Arf) is repressing HMGA2, siRNA silencing of p14(Arf) was performed resulting in a significant upregulation of HMGA2
21456046	To see if p14(Arf) can repress HMGA2 by a TP53-dependent mechanism, nutlin-3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta-galactosidase, but also decreased the expression of HMGA2, suggesting that p14(Arf) indeed influences HMGA2 by a p53-dependent mechanism because nutlin-3 stabilizes p53
21456046	As to the interaction between HMGA2 and p14(Arf) in benign tumorigenesis, we propose a model where akin to MSC self-renewal during tissue repair the simultaneous increase of p14(Arf) with HMGA2 ensures genomic stability, whereas in turn p14(Arf) can repress HMGA2 via TP53
21418545	All arrested cultures displayed three senescence markers in some cells: beta-galactosidase, nuclear p16, and heterochromatic foci/aggregates
21390332	Moreover, GR decreased expression of p16(INK4a) (p16), a well-known senescence-related gene, in all of the tested cell lines
21390332	Over-expressed p16 resulted in early replicative senescence in glucose-restricted cells suggesting a crucial role of p16 regulation in GR-induced cellular lifespan extension
21390332	The decreased expression of p16 was partly due to GR-induced chromatin remodeling through effects on histone acetylation and methylation of the p16 promoter
21390332	Furthermore, knockdown of SIRT1 abolished GR-induced p16 repression as well as Akt/p70S6K1 activation implying that SIRT1 may affect p16 repression through direct deacetylation effects and indirect regulation of Akt/p70S6K1 signaling
21363920	Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation
21363920	The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD
21341274	Senescence was associated in vivo and in vitro with oxidative damage, DNA damage foci and p16(INK4A) accumulation and required the production of reactive oxygen species (ROS), perhaps from damaged mitochondria, but not the continuous presence of the disease stimulus (areca nut and tobacco), the tissue environment or other cell types
21336312	Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli
21325480	Hepatitis B virus X protein overcomes all-trans retinoic acid-induced cellular senescence by downregulating levels of p16 and p21 via DNA methylation
21325480	The anti-senescence effect of HBx was also observed in another human hepatoma cell line, Hep3B, but not in Huh-7 cells in which the p16 and p21 proteins are absent
21325480	In addition, HBx suppressed ATRA-mediated induction of p16 and p21 in HepG2 cells via promoter hypermethylation, resulting in inactivation of retinoblastoma protein
21325480	Furthermore, the ability of HBx to overcome ATRA-induced cellular senescence almost completely disappeared when the levels of p16 and p21 in the HBx-expressing cells became similar to those in the control cells by complementation in the former by exogenous expression, knockdown of their expression in the latter using specific small interfering RNA or treatment with a DNA methylation inhibitor, 5-Aza-2'-deoxycytidine
21325480	These results suggest that HBx executes its potential by downregulating levels of p16 and p21 via DNA methylation
21325273	VentX trans-activates p53 and p16ink4a to regulate cellular senescence
21289643	Consistently, coexpression of JunB and Ras induced premature epidermal differentiation concomitant with upregulation of p16 and filaggrin and downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4)
21286718	The effects of cetuximab or irinotecan as single agents or the combination on the expression of p53, p16, and EGFR signaling pathways were also studied
21286718	The combination could also inhibit the expression of Cyclin D1 and phosphorylated mTOR while had no impact on p53, p16, PTEN, and HIF-1alpha
21276412	In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age
21263217	In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines
21263217	Moreover, cooperation of CREG1 and p16 (INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition
21263217	In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16 (INK4a) -induced senescence by transcriptional repression of cell cycle-regulated genes
21248468	Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a)
21248468	Furthermore, while the DNA/DAPI-defined SAHF formation in cultured cells parallels enhanced expression of p16(ink4a) , such 'prototypic' SAHF are not observed in tissues, including premalignant lesions, irrespective of enhanced p16(ink4a) and other features of cellular senescence
21245485	Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes
21245485	Here, by using somatic, tissue-specific inactivation of the p16(INK4a) tumor suppressor in murine T- or B-lymphoid progenitors, we report that ablation of p16(INK4a) can either rescue aging or promote cancer in a lineage-specific manner
21245485	Deletion of p16(INK4a) in the T lineage ameliorated several aging phenotypes, including thymic involution, decreased production of naive T cells, reduction in homeostatic T-cell proliferation, and attenuation of antigen-specific immune responses
21245485	Increased T-cell neoplasia was not observed with somatic p16(INK4a) inactivation in T cells
21245485	In contrast, B lineage-specific ablation of p16(INK4a) was associated with a markedly increased incidence of systemic, high-grade B-cell neoplasms, which limited studies of the effects of somatic p16(INK4a) ablation on B-cell aging
21245485	Together, these data show that expression of p16(INK4a) can promote aging and prevent cancer in related lymphoid progeny of a common stem cell
21233453	Overexpression of the cell cycle inhibitor p16INK4a promotes a prothrombotic phenotype following vascular injury in mice
21233453	In this study, we examine the contribution of p16(INK4a) overexpression to venous thrombosis
21233453	METHODS AND RESULTS: Mice overexpressing p16(INK4a) were studied with 4 different vascular injury models: (1) ferric chloride (FeCl(3)) and (2) Rose Bengal to induce saphenous vein thrombus formation; (3) FeCl(3) and vascular ligation to examine thrombus resolution; and (4) lipopolysaccharide administration to initiate inflammation-induced vascular dysfunction
21233453	Moreover, overexpression of p16(INK4a) delayed thrombus resolution compared with normal controls
21233453	In response to lipopolysaccharide treatment, the p16(INK4a) transgenic mice showed enhanced thrombin generation in plasma-based calibrated automated thrombography assays
21233453	Finally, bone marrow transplantation studies suggested increased p16(INK4a) expression in hematopoietic cells contributes to thrombosis, demonstrating a role for p16(INK4a) expression in venous thrombosis
21233453	CONCLUSIONS: Venous thrombosis is augmented by overexpression of the cellular senescence protein p16(INK4a)
21197464	JDP2 inhibits the recruitment of polycomb repressive complexes (PRC1 and PRC2) to the promoter of the gene encoding p16(Ink4a), resulting from the inhibition of methylation of lysine 27 of histone H3 (H3K27)
21188535	Senescence related genes p16, p21 and p53 increased gradually in BM-MSC
21188535	However, p16 and p53 reduced and then increased but with the gradual increase of p21 in UC-MSC
21176396	Importantly, increased p16(INK4a) following Ras upregulation was found after contact culture
21176396	ROS accumulation due to defective ROS clearance function together with Ras and p16(INK4a) upregulation play an important role in contact-induced senescence of MSCs
21099244	The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAi- transfected stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G0-G1 phase with high expression of senescence-associated beta-galactosidase
21059868	Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes
21059868	These complexes cooperate to mediate transcriptional repression of their target genes, including the Hox gene cluster and the Cdkn2a genes
21059868	Paradoxically, in embryonic fibroblasts, Pcl2 is shown to activate the expression of Cdkn2a and promote cellular senescence, presumably by suppressing the catalytic activity of PRC2 locally
21059868	Taken together, we show that Pcl2 differentially regulates Polycomb-mediated repression of Hox and Cdkn2a genes
21030557	The phenotypic and functional changes in Ews-deficient stem cells were accompanied by an increase in senescence-associated beta-galactosidase staining and a marked induction of p16(INK4a) compared with wild-type counterparts
21029119	CONCLUSION: The FACS analysis revealed a decrease in the proportion of SP cells with age, whilst p16 mRNA expression indicated an increase in cell senescence
20969773	P16INK4a was downregulated, p53 was low expressed and Bax/Bcl-2 ratio was reversed
20969773	The expression of p53 and p16INK4a in BME65Cs was altered in the pattern of down-regulation but not "loss", suggesting that this spontaneous immortalization is possibly initiated by other mechanism rather than gene mutation of p53 or p16INK4a
20959475	BRAF(V600E)-induced FOXO4 phosphorylation resulted in p21(cip1)-mediated cell senescence independent of p16(ink4a) or p27(kip1)
20956613	Moreover, a mouse model has confirmed the pivotal role of ANRIL in regulation of CDKN2A/B expression through a cis-acting mechanism and its implication in proliferation and senescence
20950777	The expression of p53 and retinoblastoma proteins is regulated by two distinct proteins, p16(Ink4a) and Arf, respectively, which are encoded by cdkn2a
20950777	JDP2 inhibits recruitment of the polycomb repressive complexes 1 and 2 (PRC-1 and PRC-2) to the promoter of the gene that encodes p16(Ink4a) and inhibits the methylation of lysine 27 of histone H3 (H3K27)
20950777	The PRCs associate with the p16(Ink4a)/Arf locus in young proliferating cells and dissociate from it in senescent cells
20950777	The molecular mechanisms that underlie the action of JDP2 in cellular aging and replicative senescence by mediating the dissociation of PRCs from the p16(Ink4a)/Arf locus are discussed
20947452	Here we show pronounced senescence in pol mu(-)(/)(-) MEFs, associated with high levels of the tumor-suppressor p16(INK4A) and the DNA damage response kinase CHK2
20938386	Total RNA isolated from these samples was used to measure the gene expression of p16INK4a, RB, cyclin D1, CDK4, PTEN, p27KIP, p19ARF, p21, TERT, and RAGE by real-time polymerase chain reaction assay
20938386	Quantitative immunohistochemical analysis showed that there were highest rates of p16INK4a and p27KIP protein expression in the cartilage endplate and anulus fibrosus of 9-month amputated rats
20938386	The mRNA levels of p16INK4a, RB, PTEN, p27KIP, p19ARF, and RAGE were upregulated
20890302	In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence
20861074	INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction
20861074	The INK4a proteins p16(INK4a) and p19(ARF) regulate cell cycle arrest and senescence
20861074	We performed unilateral ureteral obstruction (UUO) to induce fibrosis in 2- to 3-mo-old wild-type (WT) C57/B6 and INK4a knockout mice
20861074	By quantitative RT-PCR, p16(INK4a) levels were increased sixfold in WT mice 7 days after UUO and p19(ARF) remained undetectable
20861074	Kidney sections were examined to determine levels and localization of p16(INK4a), apoptosis, fibrosis, and senescent cells
20861074	INK4a knockout mice displayed mesangial cell proliferation, increased matrix deposition, and myofibroblast differentiation under normal conditions
20861074	Following UUO, INK4a knockout mice displayed 10-fold increased tubular and interstitial cell proliferation, 75% decreased collecting duct apoptosis, 2-fold greater collagen and fibronectin deposition, and no cell senescence by senescence-associated beta-galactosidase staining compared with WT mice
20861074	Both INK4a knockout mesangial cells and kidney lysates from knockout mice following injury showed elevated levels of IL-6 by ELISA compared with WT samples
20861074	INK4a knockout epithelial cell cultures displayed increased mesenchymal cell markers when exposed to transforming growth factor-beta
20841375	2 induced growth arrest without additional cellular stress in cancer cells lacking functional p53, p16, and/or Rb
20832529	CONCLUSIONS: Even though the number of biopsies analyzed for p16(INK4a) was small, it was evident that the number of cells expressing this marker of senescence was higher among biopsy specimens obtained with late rejection episodes
20808772	A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/arf locus through polycomb repressive complex 1
20808772	BACKGROUND: Polycomb group (PcG) proteins play a crucial role in cellular senescence as key transcriptional regulators of the Ink4a/Arf tumor suppressor gene locus
20808772	However, how PcG complexes target and contribute to stable gene silencing of the Ink4a/Arf locus remains little understood
20808772	Zfp277 binds to the Ink4a/Arf locus in a Bmi1-independent manner and interacts with polycomb repressor complex (PRC) 1 through direct interaction with Bmi1
20808772	Loss of Zfp277 in mouse embryonic fibroblasts (MEFs) caused dissociation of PcG proteins from the Ink4a/Arf locus, resulting in premature senescence associated with derepressed p16(Ink4a) and p19(Arf) expression
20808772	Levels of both Zfp277 and PcG proteins inversely correlated with those of reactive oxygen species (ROS) in senescing MEFs, but the treatment of Zfp277(-/-) MEFs with an antioxidant restored the binding of PRC2 but not PRC1 to the Ink4a/Arf locus
20808772	Notably, forced expression of Bmi1 in Zfp277(-/-) MEFs did not restore the binding of Bmi1 to the Ink4a/Arf locus and failed to bypass cellular senescence
20808772	CONCLUSIONS/SIGNIFICANCE: Our findings implicate Zfp277 in the transcriptional regulation of the Ink4a/Arf locus and suggest that the interaction of Zfp277 with Bmi1 is essential for the recruitment of PRC1 to the Ink4a/Arf locus
20734103	B-MYB delays cell aging by repressing p16 (INK4alpha) transcription
20734103	The expression of the p16 ( INK4alpha ) is primarily under transcriptional control
20734103	In human embryonic lung fibroblast cells, B-MYB downregulated p16 ( INK4alpha ) expression, whereas knocking down of B-MYB upregulated it
20734103	This study provides evidence of the capacity of B-MYB not only to regulate p16 ( INK4alpha ) expression but also the phenotypic consequence on cellular senescence
20723236	BACKGROUND: Chromobox 7 (CBX7) is a Polycomb family protein that extends the lifespan of normal human cells via downregulating the expression of INK4a/ARF tumor suppressor locus
20723236	METHODS: The expression of CBX7 and its potential target protein p16(INK4a) in gastric cancer cell lines and gastric tumors was assayed by Western blot analysis and immunohistochemistry(IHC)
20723236	The correlations between CBX7 expression and p16(INK4a), clinicopathological characteristics, and prognosis were analyzed
20723236	Knockdown of CBX7 expression in gastric cancer cells led to increased cellular senescence, decreased cellular proliferation and migration ability, accompanied by upregulation of p16(INK4a)
20723236	CONCLUSIONS: CBX7 acts as an oncogene in the carcinogenesis and progression of gastric cancer, and it may regulate tumorigenesis, cell migration and cancer metastasis partially via p16(INK4a) regulatory pathway
20705054	SM22alpha-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of gamma-radiation and doxorubicin in HepG2 cells
20705054	Senescence growth arrest is known to be controlled by p53 phosphorylation/p21(WAF1/Cip1) induction or p16(INK4a)/retinoblastoma protein (pRB) activation
20705054	SM22alpha overexpression in HepG2 cells elevated p16(INK4a) followed by pRB activation, but did not activate the p53/p21(WAF1/Cip1) pathway
20705054	Moreover, MT-1G, which is induced by SM22alpha overexpression, was involved in the activation of the p16(INK4a)/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents
20705054	Our findings provide the first demonstration that SM22alpha modulates cellular senescence caused by damaging agents via regulation of the p16(INK4a)/pRB pathway in HepG2 cells and that these effects of SM22alpha are partially mediated by MT-1G
20664062	We describe here the identification of a novel gene, SENEX, that regulates stress induced premature senescence pathways in endothelial cells (ECs) involving p16(INK4a) and retinoblastoma protein activation
20652617	Here, we observed that the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) caused by inhibition of histone deacetylase (HDAC) activity leads to down-regulation of high mobility group A2 (HMGA2) and, on the contrary, to up-regulation of p16(INK)(4)(A), p21(CIP)(1)(/WAF)(1) and p27(KIP)(1)
20624405	AIMS: the aims of the study are to investigate the additive effect of exogenous short-carbon chain phospholipids, C(2)-ceramide, on an anti-cancer drug paclitaxel (PTX)-induced senescence of human non-small cell lung cancer (NSCLC) cells deficient in functional p53 and p16, and to examine whether mitogen-activated protein kinase (MAPK) plays a role in ceramide-sensitized senescence of NSCLC cells
20624405	Importantly, neither p53, p21(waf1/cip1) nor p16(ink4) was shown to be involved in C(2)-ceramide-sensitized proliferative inhibition and senescence of H1299 cells by PTX in our study
20569464	Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts
20569236	The cyclin-dependent kinase inhibitor p16(INK4a) (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors
20569236	Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression
20569236	We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells
20569236	Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes
20569236	Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal
20564208	Furthermore, the requirement for Dicer in adipocyte differentiation is not due to miRNA-mediated alterations in cell proliferation, as deletion of the Ink4a locus and the prevention of premature cellular senescence normally induced in primary cells upon Dicer ablation fails to rescue adipogenic differentiation in fibroblasts and pre-adipocytes
20560902	The expression of biomarkers of DNA damage correlated positively with p16(INK4a) expression and negatively with telomere length in peripheral blood T-lymphocytes
20554622	Induction of senescence-related signal transduction proteins (p16, p21, and pRb) was examined by real-time PCR and Western blot analysis
20554622	TGF-beta2 increased p16 mRNA and protein expression, which was paralleled by a downregulation of pRb protein
20551323	Identification and characterization of Bmi-1-responding element within the human p16 promoter
20551323	One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16(Ink4a) and p19(Arf), as Bmi-1 represses the INK4a locus on which they are encoded
20551323	A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear
20551323	In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter
20551323	The BRE resided at bp -821 to -732 upstream of the p16 ATG codon
20551323	By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation
20551323	Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy
20548956	Epigenetic repression of p16(INK4A) by latent Epstein-Barr virus requires the interaction of EBNA3A and EBNA3C with CtBP
20548956	As an inhibitor of cyclin-dependent kinases, p16(INK4A) is an important tumour suppressor and inducer of cellular senescence that is often inactivated during the development of cancer by promoter DNA methylation
20548956	Using newly established lymphoblastoid cell lines (LCLs) expressing a conditional EBNA3C from recombinant EBV, we demonstrate that EBNA3C inactivation initiates chromatin remodelling that resets the epigenetic status of p16(INK4A) to permit transcriptional activation: the polycomb-associated repressive H3K27me3 histone modification is substantially reduced, while the activation-related mark H3K4me3 is modestly increased
20548956	Activation of EBNA3C reverses the distribution of these epigenetic marks, represses p16(INK4A) transcription and allows proliferation
20548956	LCLs lacking EBNA3A express relatively high levels of p16(INK4A) and have a similar pattern of histone modifications on p16(INK4A) as produced by the inactivation of EBNA3C
20548956	These novel LCLs have revealed that the chromatin remodelling and epigenetic repression of p16(INK4A) requires the interaction of both EBNA3A and EBNA3C with CtBP
20548956	The repression of p16(INK4A) by latent EBV will not only overcome senescence in infected B cells, but may also pave the way for p16(INK4A) DNA methylation during B cell lymphomagenesis
20526329	This results in the ROS-dependent activation of the p16(INK4a)/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes
20473920	Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review
20473920	A cyclin-dependent kinase inhibitor CDKN2A (p16/Ink4a) is a tumor suppressor and upregulated in cellular senescence
20473920	CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colon cancer
20473920	However, prognostic significance of CDKN2A methylation or loss of CDKN2A (p16) expression independent of CIMP status remains uncertain
20473920	Using a database of 902 colorectal cancers in 2 independent cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we quantified CDKN2A promoter methylation and detected hypermethylation in 269 tumors (30%)
20473920	By immunohistochemistry, we detected loss of CDKN2A (p16) expression in 25% (200/804) of tumors
20473920	CDKN2A promoter methylation and loss of CDKN2A (p16) were associated with shorter overall survival in univariate Cox regression analysis [hazard ratio (HR): 1
20473920	Neither CDKN2A promoter methylation nor loss of CDKN2A (p16) was associated with colorectal cancer-specific mortality in uni- or multivariate analysis
20473920	Despite its well-established role in carcinogenesis, CDKN2A (p16) promoter methylation or loss of expression in colorectal cancer is not independently associated with patient prognosis
20453494	METHODS: MGECs were subjected to H(2)O(2)-induced senescence, which was evaluated by senescence-associated beta-galactosidase (SA-beta-Gal) staining, cell cycle analysis and expression of p16
25961985	Epigenetic regulation of p16Ink4a and Arf by JDP2 in cellular senescence
25961985	Senescence is controlled mainly by gene products from the p16Ink4a/Arf locus
25961985	In mouse cells, the expression of p16Ink4a and Arf increases continuously during proliferation in cell culture
25961985	In fact, the PRCs associate with the p16Ink4a/Arf locus in young proliferating cells and dissociate in aged senescent cells
25961985	Here, we summarize the molecular mechanisms that mediate cellular aging and introduce the Jun dimerization protein 2 (JDP2) as a factor that regulates replicative senescence by mediating dissociation of PRCs from the p16Ink4a/Arf locus
20424117	EGFR overexpression triggers oncogene-induced senescence, accompanied by the induction of cyclin-dependent kinase inhibitors p15(INK4B), p16(INK4A), and p21
20424117	RNA interference directed against ZEB resulted in the induction of p15(INK4B) and p16(INK4A), reactivating the EGFR-dependent senescence program
20422055	METHODOLOGY/PRINCIPAL FINDINGS: Livers of five children aged three years or less undergoing liver transplantation due to tyrosinemia (n = 1), biliary atresia (n = 2), or fulminant hepatitis (n = 2) were analyzed for senescence associated beta-galactosidase (SA-betagal) activity and p16INK4a, p21cip1 and p53
20422055	Staining for p16(INK4a) and p21(cip1) was positive in the explanted liver of the patient with tyrosinemia, in the hepatocytes, the canals of Hering, cholangioles and interlobular bile ducts
20383119	OBJECTIVE: Our study aimed to characterize alteration in the immunohistochemical p16 expression in normal oral mucosa and non-neoplastic hyperproliferative disorders (i
20383119	However, when the patient's tobacco smoking was examined, p16 nuclear staining in oral epithelium was seen in 4/20 (20%) of smokers and 0/23 (0%) of non-smokers
20383119	In clinically normal oral epithelium of smokers and in frictional keratosis, basal and supra-basal cells expressed strong p16 nuclear staining which was absent in the control tissue examined
20383119	CONCLUSION: Our data suggest that p16 expression may be involved in the long-term loss of proliferation in cell senescence of oral mucosa
20376899	They also showed increased p16 expression, decreased metabolic activity, and cell growth retardation
20376899	Human skin tissue from elderly persons showed decreased moesin expression and increased p16 expression
20354187	JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-kappaB
20348948	TBX2 has previously been shown to repress growth control genes such as p14(ARF) and p21(WAF1/cip1)
20331441	Here, we show that mouse tissues exposed to a sublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage foci and increased p16(INK4a) expression, two hallmarks of cellular senescence and aging
20164124	This induction is associated with higher levels of p16(INK4A) and phosphorylated p53
20164124	Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC
20157424	In cultured primary human fibroblasts, for example, ectopic expression of oncogenic Ras or its downstream mediator initiates cellular senescence, the state of irreversible cell cycle arrest, through up-regulation of cyclin-dependent kinase (CDK) inhibitors, such as p16(INK4a)
20157424	To date, much of our current knowledge of how human p16(INK4a )gene expression is induced by oncogenic stimuli derives from studies undertaken in cultured primary cells
20157424	However, since human p16(INK4a )gene expression is also induced by tissue culture-imposed stress, it remains unclear whether the induction of human p16(INK4a )gene expression in tissue-cultured cells truly reflects an anti-cancer process or is an artifact of tissue culture-imposed stress
20157424	To eliminate any potential problems arising from tissue culture imposed stress, we have recently developed a bioluminescence imaging (BLI) system for non-invasive and real-time analysis of human p16(INK4a )gene expression in the context of a living animal
20157424	Here, we discuss the molecular mechanisms that direct p16(INK4a )gene expression in vivo and its potential for tumor suppression
20146798	These senescent cells display increased size, contain senescence associated beta-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16)
20146798	Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated beta-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent
20146798	Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored
20146798	RESULTS: Cultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated beta-galactosidase or p16 expression, than cultures derived from unirradiated cells
20146798	As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures
20118236	Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53/ARF pathway disruption in spontaneous escape from senescence
20069554	Hydrogen peroxide induces p16(INK4a) through an AUF1-dependent manner
20069554	Elevation of p16(INK4a) has been described as an important mechanism for hydrogen peroxide (H2O2)-induced replicative senescence
20069554	In this study, we demonstrate an important role of RNA-binding protein AUF1-mediated mRNA turnover in H2O2-induced p16(INK4a) expression
20069554	The induction of p16 by H2O2 was accompanied with declined cytoplasmic AUF1 level
20069554	Accordingly, exposure of cells to H2O2 remarkably reduced the binding of AUF1 to p16 3'UTR and increased the half-life of an EGFP-p16-3'UTR chimeric transcript
20069554	In AUF1-silenced cells, the effect of H2O2 on p16 induction was abolished
20069554	Furthermore, in cells co-transfected with vectors expressing AUF1s, treatment with H2O2 failed to significantly reduce the expression of AUF1 and subsequently elevate the levels of p16
20069554	Our results indicate that AUF1 is critical for H2O2-induced p16 expression and cellular senescence
20049504	These results suggest that HDAC activity might be important for MSC self-renewal by balancing PcGs and JMJD3 expression, which govern cellular senescence by p16(INK4A) regulation
21368868	Dex upregulates cell cycle-related genes p16 and p21 in a glucocorticoid receptor(GR)-dependent manner
20034468	Most of the MSCs cultured under normoxic conditions were in a senescent state after 100days, while few senescent cells were found in the hypoxic culture, which was associated with a down-regulation of p16 gene expression
20034468	Among the molecules related to mitogen-activated protein kinase (MAPK) signaling pathways, extracellular signal regulated kinase (ERK) was significantly down-regulated by hypoxia, which helped to inhibit the up-regulation of p16 gene expression
20034468	Therefore, the hypoxic culture retained MSCs in an undifferentiated and senescence-free state through the down-regulation of p16 and ERK
20016134	There were positive correlations between the percentages of senescent type II cells that expressed p16(INK4a) and the percentages of type II cells that expressed phosphorylated NF-kappaB
20010815	In MEFs, Myc-induced senescence was genetically dependent on the ARF-p53-p21Cip1 and p16INK4a-pRb pathways, p21Cip1 and p16INK4a being selectively induced in Cdk2-/- cells
19954516	EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence
19954516	RESULTS: We found that INK4b and INK4a, but not ARF, are upregulated following the differentiation of haematopoietic progenitor cells, in ageing fibroblasts and in senescing malignant rhabdoid tumour cells
19954516	As we described earlier, PcG repressors bind the INK4a promoter, but not ARF
19954516	During progenitor cell differentiation and ageing, PcG silencer EZH2 attenuates, causing loss of PRC binding and transcriptional activation of INK4b and INK4a
19954516	In the repressed state, the PRC-binding regions are in close proximity, while the intervening chromatin harbouring ARF loops out
19954516	Down regulation of EZH2 causes release of the approximately 35 kb repressive chromatin loop and induction of both INK4a and INK4b, whereas ARF expression remains unaltered
19954516	CONCLUSION: PcG silencers bind and coordinately regulate INK4b and INK4a, but not ARF, during a variety of physiological processes
19948976	Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53
21994573	The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21(Cip1) and p16(INK4a)/pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage
19907431	By evaluating the molecular pathways of senescence in relation to proliferative potential of primary keratinocyte cultures from young and old healthy donors, and from young patients with inherited defects leading to premature aging, we demonstrated that p16(INK4a) is a reliable marker of both physiological and premature epidermal aging
19907431	Analysis of the expression and activity of p16(INK4a) regulators showed that stem cell depletion, reduced proliferation, and p16(INK4a) upregulation in keratinocytes derived from the chronologically and prematurely aged epidermis strongly correlate with Bmi-1 downregulation
19907431	Our findings demonstrated that Bmi-1 is downregulated in human keratinocytes during both in vitro processes, in parallel with p16(INK4a) upregulation and accomplishment of clonal conversion
19907431	Moreover, Bmi-1 inhibited Ets-1-mediated p16(INK4a) upregulation
19907431	Finally, Bmi-1 overexpression reduced p16(INK4a) promoter activity and decreased protein expression in aged and diseased keratinocytes, inducing a delay of clonal conversion and an increase of cell clonogenic ability
19856145	By recombining fractionated components from senescent and low-passage cells, we found that in senescence the membrane component is defective in activating PLD implicating either the PLD enzyme itself or its interaction with PKC and/or ARF
19850045	Significantly diminished foci numbers coupled with massive senescence/growth arrest and elevated expression of cyclin-dependent kinase inhibitors (CDKIs) p21(CIP1), p27(kip1), and/or p16(ink4a) occurred in RBP2-depleted gastric and cervical cancer cells
19826180	Salt-induced cardiac remodelling was associated with 4-fold increase in cardiac p16(INK4a) mRNA expression, a marker of cellular senescence
19748549	MATERIALS AND METHODS: We have analyzed the expression of p16INK4a in bone marrow mononuclear cells or CD34(+) cells from 53 patients with MDS, 12 acute myeloid leukemia (AML), and 11 healthy controls
19748549	RESULTS: An upregulated expression of senescence-associated molecular marker p16INK4a was found in MDS compared with healthy controls, while a lower expression of p16INK4a was observed in AML compared with healthy controls
19730126	Postinfarct cardiac remodeling was associated with increased atrial natriuretic peptide, interleukin-6 and connective tissue growth factor mRNA expressions, as well as three-fold increased cardiomyocyte senescence, measured as cardiac p16 mRNA expression
19723773	Interestingly, nocodazole (NCZ), which induces G2/M block, increased the percentage of senescent cells as well as the expression of miR-290 and of the tumor suppressor p16, thus mimicking culture senescence
19723773	Whereas the induction of SA-beta-gal(+) by miR-290 was not strengthened by coupling its transfection with NCZ treatment, the transfection of the antagomir 290 (d-290) plus NCZ treatment, while blocking cells at G2/M, suppressed SA-beta-gal(+) and p16 induction
19723773	On the basis of these findings we conclude that miR-290 might act as a physiological effector of NCZ induced as well as culture senescence via p16 regulation expanding the role of this miRNA from embryonic stem to differentiated cells
19710698	Unfortunately, however, tumors including adult T-cell leukemia/lymphoma (ATL) have disadvantages such as p53 mutations and a lack of p16(INK4a) and/or p14(ARF)
19710698	Interestingly, senescence-associated-beta-galactosidase (SA-beta-gal) staining revealed that only ATL-related cell lines with wild-type p53 showed cellular senescence, although they lack both p16(INK4a) and p14(ARF)
19710698	These results indicate that cellular senescence is an important event in p53-dependent cell death in ATL cells and is inducible without p16(INK4a) and p14(ARF)
19690330	Consistent with the effect of p19(Arf) loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14(ARF) (the human equivalent of mouse p19(Arf))
19689470	The expression level of p16(INK4A), a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment
19656618	Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16(INK4a) expression via DNA methylation
19656618	HBx induced DNA hypermethylation of p16(INK4a) promoter and subsequently interfered action of transcription factors like Ets1 and Ets2 activated by H(2)O(2) through the p38(MAPK) pathway, resulting in inhibition of its transcription
19656618	Down-regulation of p16(INK4a) expression by HBx subsequently led to activation of G(1)-CDKs, phosphorylation of Rb, activation of E2F1, and finally evasion from G(1) arrest induced by H(2)O(2)
19656618	In addition, the potentials of HBx to inactivate Rb and subsequently inhibit cellular senescence almost completely disappeared when levels of p16(INK4a) were recovered either by exogenous complementation or inhibition of the promoter hypermethylation
19656618	To our knowledge, our present study represents the first report that an oncogenic virus evades cellular senescence through epigenetic down-regulation of p16(INK4a) expression
19648966	Activation of different upstream pathways by overexpression of either p21 or p16 converged on Rb2/p130 accumulation and induced senescence
19636380	Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus
19636380	Misexpression of Polycomb repressive complex 1 (PRC1) components in human cells profoundly influences the onset of cellular senescence by modulating transcription of the INK4a tumor suppressor gene
19636380	Using tandem affinity purification, we find that CBX7 and CBX8, two Polycomb (Pc) homologs that repress INK4a, both participate in PRC1-like complexes with at least two Posterior sex combs (Psc) proteins, MEL18 and BMI1
19636380	In primary human fibroblasts, CBX7, CBX8, MEL18 and BMI1 are present at the INK4a locus and shRNA-mediated knockdown of any one of these components results in de-repression of INK4a and proliferative arrest
19616052	We found that simulated microgravity induced partial G1 phase arrest, upregulated senescence-associated beta-galactosidase (SA-beta-gal) activity, and activated both p53 and p16 protein pathways linked to cell senescence
19583777	The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence
19583777	In this article, we demonstrate that ZBP-89 was able to restrain senescence in NCI-H460 human lung cancer cells, through epigenetically regulating p(16INK4a) expression
19583777	Specifically, our results indicate that knockdown of ZBP-89 by RNA interference stimulated cellular senescence in NCI-H460 cells, as judged by the senescence-associated beta-galactosidase activity assay and senescence-associated heterochromatin foci assay, and this process could be reversed by RNA interference-mediated p16(INK4a) silencing
19583777	We also show that histone deacetylase (HDAC) 3 and HDAC4 inhibited p16(INK4a) promoter activity in a dose-dependent manner
19583777	Furthermore, chromatin immunoprecipitation assays verified that HDAC3 was recruited to the p16(INK4a) promoter by ZBP-89 through an epigenetic mechanism involving histone acetylation modification
19583777	These data suggest that ZBP-89 and HDAC3, but not HDAC4, can work coordinately to restrain cell senescence by downregulating p16(INK4a) expression through an epigenetic modification of histones
19564843	Cultured HGECs treated with lysolecithin, the level of which is elevated in gallbladder bile of PBM, showed increased expression of p16(INK4A) and senescence-associated beta-galactosidase
19564843	Conversely, enforced overexpression of EZH2 in senescent HGECs reduced p16(INK4A) expression
19564843	A knockdown of EZH2 in cultured TGBC2TKB cells increased p16(INK4a) expression
19540815	OUTCOME MEASURES: We examined cell senescence markers (senescence-associated beta-galactosidase [SA-beta-gal], telomere length, telomerase activity, p53, p21, pRB, and p16) and the hydrogen peroxide (H(2)O(2)) content as a marker for an oxidative stress in the human NP specimens
19540815	For the mechanism involved in the senescence of NP chondrocytes, expressions of p53, p21, pRB, and p16 in these cells were assessed with immunohistochemistry and Western blotting
19540815	Immunohistochemistry showed that the senescent NP chondrocytes in all the specimens expressed p53, p21, and pRB, but a few NP chondrocytes in only two specimens expressed p16
19486941	Adaptive responses and loss of checkpoint proteins such as p53 and p16(INK4a) allow tumor cells to tolerate constitutive mitogenic signaling and enhanced production of ROS, leading to altered redox status in many fully transformed cells
19471117	In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21
19471117	Thus, when the cell cycle was arrested by these factors in the presence of rapamycin, cells retained the capacity to resume proliferation, once p21, p16 or sodium butyrate were removed
19451218	Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS
19451218	The INK4a/ARF tumor suppressor locus, a key executor of cellular senescence, is regulated by members of the Polycomb group (PcG) of transcriptional repressors
19451218	Here we show that signaling from oncogenic RAS overrides PcG-mediated repression of INK4a by activating the H3K27 demethylase JMJD3 and down-regulating the methyltransferase EZH2
19451218	In human fibroblasts, JMJD3 activates INK4a, but not ARF, and causes p16(INK4a)-dependent arrest
19451218	In mouse embryo fibroblasts, Jmjd3 activates both Ink4a and Arf and elicits a p53-dependent arrest, echoing the effects of RAS in this system
19451218	Our findings directly implicate JMJD3 in the regulation of INK4a/ARF during oncogene-induced senescence and suggest that JMJD3 has the capacity to act as a tumor suppressor
19451217	The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are key regulators of cellular senescence
19451217	JMJD3 is recruited to the INK4A-ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts
19451217	Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization
19445133	The population doublings of 2BS cells were observed, the mRNA expression of P16 gene was determined by fluorescence real-time quantitative PCR
19445133	RESULTS: FG significantly extended the population doublings of 2BS cells, and decreased the expression of P16 mRNA
19445133	CONCLUSION: FG can delay the senescence of cells by inhibiting the P16 gene expression
19398954	Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A)
19398954	Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs)
19398954	We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level
19398954	Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells
19398954	Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo
19396980	The tumor suppressors p16(INK4a) and p53 have been implicated as contributors to age-associated stem cell decline
19396980	Aged tissues of p53(+/m) mice display higher percentages of senescent cells (as determined by senescence-associated beta-galactosidase staining and p16(INK4a) and p21 accumulation) compared to aged tissues from p53(+/+) mice
19396980	Ionizing radiation treatment of p53(+/m) tissues also induces higher and prolonged levels of senescence markers p16(INK4a) and p21, suggesting that in p53(+/m) tissues the p53 stress response is enhanced and is shifted away from apoptosis toward senescence
19381346	Our results also indicate that the p16(INK4a) signaling pathway may play a key role in the early stages of senescence in CECs while the p53/p21(WAF1/CIP1) signaling pathway may exert its principle effect in the late stages of senescence in CECs
19345325	Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis
19340300	A functional screen for regulators of CKDN2A reveals MEOX2 as a transcriptional activator of INK4a
19340300	The CDKN2A locus encodes two important tumor suppressors, INK4a and ARF, which respond to oncogenic stresses by inducing cellular senescence
19340300	We conducted a genome-scale cDNA overexpression screen using a reporter containing INK4a regulatory sequences to identify novel transcriptional activators of this locus
19340300	We further demonstrate that MEOX2-induced senescence is dependent upon INK4a activity, and chromatin immunoprecipitation studies indicate that MEOX2 directly binds the INK4a promoter
19340300	These results support a role for this homeodomain protein as a direct regulator of INK4a transcription and senescence in human cells
19269967	Overexpression of BMP4 was able to induce premature senescence in lung cancer cells and this process required the participation of cyclin/cyclin-dependent kinase (cdk) inhibitors p16(INK4a) and p21(WAF1/cip1)
19269967	We also show that increases of p16(INK4a) and p21(WAF1/cip1) expression in response to BMP4 were mediated by the Smad signaling pathway
19235838	When FoxM1 in gastric cancer cells was knocked-down, impaired clonogenicity and cellular senescence occurred independently of p53 and p16 status
19217096	MAIN OUTCOME MEASURE(S): Senescence measured by percentage of SA-beta-Gal-positive cells; levels of let-7 microRNAs measured by RT-PCR and MISH; expression of p16(INK4a), Ki-67, HMGA1, and HMGA2 scaled by immunoreactivity
19208841	DDB1-CUL4 and MLL1 mediate oncogene-induced p16INK4a activation
19208841	The induction of cellular senescence by oncogenic signals acts as a barrier to cellular transformation and is attained, in part, by the elevation of the p16(INK4a) tumor suppressor gene
19208841	We report here that the p16 locus is H3K4-methylated in highly expressing cells
19208841	H3K4 methyltransferase MLL1 directly binds to and is required, along with its core component RbBP5, for the induction of p16 by oncogenic Ras
19208841	We showed that CUL4A directly binds to p16 and that silencing DDB1 blocks Ras-induced p16 activation
19208841	Ras expression dissociates BMI1 from the p16 locus, whereas both CUL4 and MLL1 bind to the p16 locus similarly in both normal and oncogenic stimulated cells
19208841	These results suggest that DDB1-CUL4 and MLL1 complexes constitute a novel pathway that mediates p16 activation during oncogenic checkpoint response and is repressed by the polycomb repression complexes during normal growth of young cells
19181515	Both the DNA damage response and the ARF tumor suppressor have been mechanistically implicated in oncogene-induced senescence and the relative contributions of, and potential interactions between, these two pathways remain subjects of a lively debate
19171648	Expression of senescence-associated genes (apolipoprotein J [Apo J], connective tissue growth factor [CTGF], fibronectin, and SM22) was examined by real-time PCR and induction of signal transduction proteins (p21, p16, and pRb) by Western blot analysis
19171648	In contrast, they had no effect on p16 expression
19164294	The Cspg2(Delta3/Delta3) fibroblasts showed a substantial increase of ERK1/2 phosphorylation and expression of senescence markers p53, p21, and p16
19133932	Before transplantation, old kidneys were histologically normal, but displayed an increased expression of senescence marker p16(INK4a)
19133932	Old allografts at day 7 showed a more rapid emergence of epithelial changes and a further increase in the expression of p16(INK4a)
19133932	The expression of p16(INK4a) remained low in young kidney allografts at day 7, but increased with severe rejection at day 21
19133932	Isografts from young donors showed no epithelial changes and no increase in p16(INK4a)
19133932	Thus, old donor kidneys display abnormal parenchymal susceptibility to transplant stresses and enhanced induction of senescence marker p16(INK4a), but were not more immunogenic
19130492	Phenotype-rescue of cyclin-dependent kinase inhibitor p16/INK4A defects in a spontaneous canine cell model of breast cancer
19130492	In contrast, expression of p16/INK4A was defective/absent in two cell lines and normal/slightly induced in the third cell line
19130492	To determine if defects were causative in maintaining the transformed phenotype, a p16/INK4A transgene was permanently transfected followed by selection and single cell cloning
19130492	CMT/p16 clones were characterized for transgene expression, p16 protein content and phenotype including proliferation rate, cell cycle phase distribution, contact inhibition, substrate dependent cell growth and cell morphology
19130492	All cell lines appeared unique yet clear indications of phenotype rescue due to p16/INK4A transgene complementation were observed suggesting that defects in p16 expression were present in all three
19130492	These data provide evidence supporting p16/INK4A mutations as causative defects promoting transformation in canine mammary cancer and further characterizes tumor suppressor gene defects with functional consequences in these cells supporting their application as spontaneous animal models of human disease
19126595	Markers of cellular senescence p21 and p16 were also increased (P<0
19124561	However, EPCs up-regulated the expression of the senescence-associated cell cycle arrest protein p16(INK4a) and markedly increased measured senescence levels when exposed to chronic TNF-alpha treatment
19122829	In addition, HDAC inhibitors induced the senescence of corneal myofibroblasts as shown by enhanced staining of beta-galactosidase and upregulated expression of p16(ink4a)
19118192	This senescent phenotype recapitulated several salient features of replicative senescence, notably the presence of senescence-associated beta-galactosidase (SA beta-gal) activity, apparently irreparable genomic DNA breaks, and elevation of p21(Cip1), p53, and p16(INK4A) tumor suppressor protein levels
19099650	Morphology, senescence-associated beta-galactosidase (SA-beta-gal) staining and cell cycle analysis were used to evaluate the changes in BMMSCs at cellular level while real-time RT-PCR was used to detect the alterations in senescence related gene expression including p16INK4a, p21Cip1/Waf1, p53 and TGF-beta1
19070423	Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation
19070423	Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a)
19067655	We have tested this hypothesis in a cohort of preimplantation human renal allograft biopsies ( n = 75) that have been assayed by real-time polymerase chain reaction for the expression of known markers of cellular damage and biological aging, including CDKN2A, CDKN1A, SIRT2 and POT1
19067655	Linear regression analyses indicated a strong association for serum creatinine with pre-transplant CDKN2A levels ( p = 0
19067655	Multiple linear regression analyses for CDKN2A and donor age accounted for 24
18983959	Ink4a/Arf regulation by let-7b and Hmga2: a genetic pathway governing stem cell aging
18983959	In a recent issue of Cell, Nishino and colleagues (2008) show that Hmga2 maintains neural stem cell (NSC) function in young mice through repression of the Ink4a/Arf locus; in contrast, during aging, elevated let-7b blocks Hmga2 and contributes to declining NSC function
18948382	Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence
18843795	Senescence can be overcome if the pathway is not fully engaged, and this may occur when p16(INK4a) is inactivated
18843795	To characterize the functions of melanoma-associated p16(INK4a) mutations, in terms of promoting proliferative arrest and initiating senescence, we utilized an inducible expression system in a melanoma cell model
18843795	We show that wild-type p16(INK4a) promotes rapid cell cycle arrest that leads to a senescence programme characterized by the appearance of chromatin foci, activation of acidic beta-galactosidase activity, p53 independence and Rb dependence
18843795	Accumulation of wild-type p16(INK4a) also promoted cell enlargement and extensive vacuolization independent of Rb status
18843795	In contrast, the highly penetrant p16(INK4a) variants, R24P and A36P failed to arrest cell proliferation and did not initiate senescence
18843795	We also show that overexpression of CDK4, or its homologue CDK6, but not the downstream kinase, CDK2, inhibited the ability of wild-type p16(INK4a) to promote cell cycle arrest and senescence
18843795	Our data provide the first evidence that p16(INK4a) can initiate a CDK4/6-dependent autonomous senescence programme that is disabled by inherited melanoma-associated mutations
18836285	Whether or not such neoplasms progress to malignancy or persist in a benign state for many years might be largely determined by the outcome of this tug of war and its modulation by other genetic and epigenetic alterations, such as inactivation of p16(INK4a)
18769141	The yin and yang of the Cdkn2a locus in senescence and aging
18769141	This, together with the observation that p19(Arf) and p16(Ink4a) expression increases with age in many tissues of humans and rodents, led to the speculation that these pathways drive in vivo senescence and natural aging
18769141	Importantly, BubR1 hypomorphism elevates both p16(Ink4a) and p19(Arf) expression in skeletal muscle and fat
18769141	Inactivation of p16(Ink4a) in BubR1 mutant mice delays both cellular senescence and aging specifically in these tissues
18769141	These mouse studies suggest that p16(Ink4a) is indeed an effector of aging and in vivo senescence, but p19(Arf) an attenuator
18768588	As a first step, we studied whether the senescence-associated beta-galactosidase (SA-beta-Gal) and the cell cycle inhibitor p16INK4A are induced in renal biopsies from patients with type 2 DN
18768588	P16INK4A expression was significantly increased in tubules (P < 0
18768588	Nuclear p16INK4A in glomeruli was associated with proteinuria (P < 0
18768588	In a parallel set of experiments, proximal tubule cells passaged under high glucose presented a limited life span and an approximately twofold increase in SA-beta-Gal and p16INK4A protein
18706112	The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53
18706112	RESULTS: The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists
18706112	CONCLUSION: The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions
18691180	Phenotypic effects may result from differential effects on gene expression since ING1a increases levels of both retinoblastoma and the p16 cyclin-dependent kinase inhibitor and ING1a and ING1b have opposite effects on the expression of proliferating nuclear cell antigen (PCNA), which is required for cell growth
18681962	The correlation between caveolin-1 and p16INK4a (biomarker of cellular senescence) gene expression was investigated using quantitative real-time PCR
18681962	A positive correlation was identified between gene expression of caveolin-1 and p16INK4a
18678645	Overexpression or knockdown of CSIG did not influence p21(Cip1) and p16(INK4a) expressions
18673371	Cells from different culture passages (P6 and P16) were treated with PDRN at different experimental times
18673371	RESULTS AND CONCLUSIONS: PDRN seemed to promote proliferation of human pre-adipocytes at both passages, but cell population growth increased in pre-adipocyte at P16, after 9 days as compared to control
18628455	RESULTS: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence
18628455	TAC clones with reduced p16 expression successfully bypassed this phase
18628455	We further found close correlation between the levels of junB and p16 expression
18628455	Repeated transfection of junB siRNA in prostatic TAC allowed the cells to escape senescence presumably through inactivation of p16/pRb
18628455	CONCLUSIONS: JunB is an essential upstream regulator of p16 and contributes to maintain cell senescence that blocks malignant transformation of TAC
18607883	Thus, a large number of cells enter senescence in premalignant lesions but none do so in malignant tumors, due to the loss of senescent pathway effectors such as p16(INK4a) or ARF-p53
18587721	Studies support a central role for Rb protein in controlling this process via signaling from the p53 and p16 pathways
18558095	YY1 restrained cell senescence through repressing the transcription of p16
18558095	In this report, we demonstrate that YY1 was able to suppress NCI-H460 cell senescence through regulating the expression of p16(INK4a), a cyclin-dependent kinase inhibitor
18558095	We also show that YY1 participated in the repression of p16(INK4a) expression in 293T cells through an epigenetic mechanism involving histone acetylation modification
18558095	Specifically, HDAC3 and HDAC4 inhibited the p16(INK4a) promoter activity
18558095	The chromatin immunoprecipitation (ChIP) assays verified that HDAC3 and HDAC4 were recruited to p16(INK4a) promoter by YY1
18558095	Overall, data from this study suggest that YY1, HDAC3 and HDAC4 restrained cell senescence by repressing p16(INK4a) expression through an epigenetic modification of histones
18544633	Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in the inhibition of cell growth by promoting cell-cycle arrest, and PPARgamma activation induces the expression of p16(INK4alpha) (CDKN2A), an important cell-cycle inhibitor that can induce senescence
18544633	PPARgamma can bind to the p16 promoter and induce its transcription, and, after treatment with a selective PPARgamma agonist, we observed more-robust expression of p16(INK4alpha) in senescent cells than in young cells
18516091	Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
18516091	Expression of p16(Ink4a) and p19(Arf) increases with age in both rodent and human tissues
18516091	However, whether these tumour suppressors are effectors of ageing remains unclear, mainly because knockout mice lacking p16(Ink4a) or p19(Arf) die early of tumours
18516091	Here, we show that skeletal muscle and fat, two tissues that develop early ageing-associated phenotypes in response to BubR1 insufficiency, have high levels of p16(Ink4a) and p19(Arf)
18516091	Inactivation of p16(Ink4a) in BubR1-insufficient mice attenuates both cellular senescence and premature ageing in these tissues
18516091	Thus, we identify BubR1 insufficiency as a trigger for activation of the Cdkn2a locus in certain mouse tissues, and demonstrate that p16(Ink4a) is an effector and p19(Arf) an attenuator of senescence and ageing in these tissues
20411135	METHODS: We examined cell senescence markers [senescence-associated beta-galactosidase (SA-beta-gal), telomere length, telomerase activity, p53, p21, pRB and p16] and the hydrogen peroxide (H(2)O(2)) content in human NP specimens
20411135	Immunohistochemistry showed that senescent NP chondrocytes in all specimens expressed p53, p21, and pRB, while a few NP chondrocytes in only two specimens expressed p16
20411135	Furthermore, the telomere-based p53, p21, pRB pathway, rather than the stress-based p16, pRB pathway, plays a more important role in the senescence of NP chondrocytes in in vivo conditions
18504326	Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a
18504326	Cell cycle inhibitor p16(INK4a) is the key mediator for stress and aberrant signaling induced senescence
18504326	Here we report that elevated blood pressure markedly induced p16(INK4a) expression in rat kidneys and hearts, as well as in human kidneys
18504326	In kidneys from deoxycorticosterone acetate-salt-treated rats, p16(INK4a) induction was found in tubular, glomerular, interstitial, and vascular cells and correlated with the typical histopathologic features of hypertensive target organ damage
18504326	In left ventricles, increased p16(INK4a) expression was found in myocardium and cardiac arteries
18504326	Antihypertensive medication consistent of hydrochlorothiazide, hydralazine, and reserpine ameliorated the histopathologic changes and attenuated p16(INK4a) expression in kidneys of deoxycorticosterone acetate-salt-treated rats
18504326	Nonantihypertensive administration of spironolactone also reduced kidney damage and p16(INK4a) expression
18504326	In human kidney biopsies showing hypertensive nephrosclerosis, increased p16(INK4a) expression was found compared with age-matched normotensive control subjects
18488334	OBJECTIVE: To investigate the expressions of the aging gene P16(ink4a) and anti-aging gene HST2 in benign prostatic hyperplasia (BPH)
18488334	The expressions of P16(ink4a) was detected by semi-quantitative analysis in BPH and normal prostate tissues
18488334	RESULTS: P16(ink4a) mRNA, rather than HST2, was expressed in the BPH and normal prostate tissues
18488334	Semi-quantitative analysis showed that the P16(ink4a) mRNA expression in the normal prostate tissues (0
18488334	CONCLUSION: P16(ink4a) might play an important role in the pathogenesis of BPH and is probably one of the factors of cell aging escape
18462273	Telomere length and mRNA expression levels of the cell cycle inhibitors CDKN2A (p16INK4a) and CDKN1A (p21WAF1) were assessed in pre-implantation biopsies of 54 patients and the association of these and various other clinical parameters with serum creatinine after 1 year was determined
18462273	In a linear regression analysis, CDKN2A turned out to be the best single predictor followed by donor age and telomere length
18462273	A multiple linear regression analysis revealed that the combination of CDKN2A values and donor age yielded even higher predictive values for serum creatinine 1 year after transplantation
18462273	We conclude that the molecular aging marker CDKN2A in combination with chronological donor age predict renal allograft function after 1 year significantly better than chronological donor age alone
18425358	FACS analysis showed that UVB-stressed HSFs were blocked mostly in the G1 phase of the cell cycle, and replicative senescence, and protein expression of p53, p21(WAF-1) and p16(INK-4a) increased significantly
18391207	IMR-90 fibroblast populations cultured in magnesium-deficient conditions had increased senescence-associated beta-galactosidase activity and increased p16(INK4a) and p21(WAF1) protein expression compared with cultures from standard media conditions
18378907	Deletion of the p19(ARF), p53, or p21(WAF1) tumor suppressors but not p16(INK4a) prevented senescence and permitted tumorigenesis
18372918	Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression
18372918	Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model
18353141	Loci with established importance in melanoma, like CDKN2A, BRAF and PTEN, have been joined by some less familiar genes including transcription factor sequences TBX2 and STK11 (LKB)
18332116	We found previously that, in MRT cells, hSNF5 is required for p16(INK4a) induction, mitotic checkpoint activation, and cellular senescence
18320031	Western blot results showed that SIRT1 reduced the expression of p16(INK4A) and promoted phosphorylation of Rb
18316603	Two nucleolar proteins, p14(ARF)/p19(ARF) and B23, were shown to translocate out of the nucleolus after exposure of cells to DNA-damaging agents
18316603	The stress-induced translocation of alternative reading frame (ARF) is JNK dependent and mediated by two activator proteins, c-Jun and JunB
18316603	Hence, we suggest that c-Jun translocates B23 and ARF from the nucleolus after JNK activation by means of protein interactions
18316603	In senescent cells, JNK activity and c-Jun levels are reduced concomitantly with ARF nucleolar accumulation, and UV radiation does not cause the translocation of ARF
18314458	Plaques were analyzed for ubiquitin levels, proteasome 20S activity, p16 and p53, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay)
18298915	Two isomers of HDTIC isolated from Astragali Radix decrease the expression of p16 in 2BS cells
18298915	METHODS: The effects of HDTIC-1 and HDTIC-2 on the expression of p16 and p21 were observed in vitro by RT-PCR and Western blot
18298915	RESULTS: There was an obvious expression of p16 in the control senescent cells
18298915	CONCLUSIONS: Expression of p16 by 2BS cells was strongly inhibited by HDTIC compounds, which could contribute to their delayed replicative senescence by the way of p16(INK4a)/Rb/MAPK
18298915	The anti-oxidative activities of HDTIC-1 and HDTIC-2, described in this study for the first time, might be indirectly related to their inhibition of p16 expression
18240291	We have previously shown that Id1 delays cellular senescence in primary mammalian cells through inhibition of the cell cycle regulatory protein and familial melanoma gene, p16/INK4a
18240291	Here we show that constitutive expression of Id1 in primary human melanocytes leads to delayed cellular senescence and decreased expression of the familial melanoma gene, p16/INK4a
18240291	We conclude that Id1 delays cellular senescence in primary human melanocytes through inhibition of p16/INK4a expression and suggest that Id1 may contribute to the malignant conversion of primary human melanocytes through extension of cellular lifespan
18196872	Cisplatin-induced senescence and growth inhibition in human non-small cell lung cancer cells with ectopic transfer of p16INK4a
18196872	In this work, the highly tumorigenic and cisplatin-resistant human non-small cell lung cancer (NSCLC) cells were transfected with construct encoding the complete sequence of p16INK4a (p16)
18196872	The stable clones with elevated p16 exhibited enhanced sensitivities to low concentration cisplatin treatment
18196872	Further study indicated that cisplatin arrested cells at G2/M phase and the effectiveness is proportional to the level of p16 expressed
18196872	The growth of the xenograft tumors established by p16 transfectants in nude mice was also suppressed by cisplatin by inducing senescence-like phenotype
18196872	The data altogether indicated that, in cisplatin-resistant tumor cells with basal endogenous p16, the growth suppression by drugs can be greatly improved by ectopic gene transfer
18192284	Replicative senescence in MEFs is classically triggered by products of the Ink4a (Cdkn2a) gene
18192284	However, this Ink4a pathway is not activated during senescence of Zeb1 mutant MEFs
18164318	Reactivation of methylation-silenced tumor suppressor gene p16INK4a by nordihydroguaiaretic acid and its implication in G1 cell cycle arrest
18164318	Our results indicated that NDGA reverses p16INK4a CpG island hypermethylation, and restores its transcription and expression in both cell lines
18164318	Consistent with the reacquisition of p16INK4a expression, we also found that NDGA induces cellular senescence in cancer cells
18076574	Polycomb complexes regulate cellular senescence by repression of ARF in cooperation with E2F3
18076574	Mel18-null MEFs undergo typical premature senescence accompanied by the up-regulation of ARF/p53/p16(INK4a) and decrease of Ring1b/Bmi1
18076574	Our results demonstrated that ARF or p53 deletion cancels the senescence in Mel18-null MEFs, and the fact that p16(INK4a) is up-regulated in double-null MEFs suggests that the ARF/p53 pathway plays a central role in stress-induced senescence
18076574	The in vivo binding of Ring1b and E2F3b to the ARF promoter decreased progressively in senescence, and Mel18 inactivation accelerated the exfoliation of Ring1b/E2F3b from the promoter sequence, indicating the cooperation of polycombs/E2F3b on ARF expression and cellular senescence
18076574	Taken together, it seems that class II polycomb proteins and E2F3b dually control cellular senescence via the ARF/p53 pathway
17939921	Here we discuss the function and regulation of the tumor suppressor proteins INK4a/ARF in connection with replicative senescence, cancer and aging
17913706	However, ca-STAT5A did not induce p21 and p16(INK4a), which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras
17804819	Premature senescence induced by IGFBP-5 up-regulation in young cells was rescued by knockdown of p53, but not by knockdown of p16
17761140	Reduced expression of INK4a/ARF genes in stem-like sphere cells from rat sarcomas
17721438	Importantly, knockdown of either p53 or p21Cip1, but not p16(INK4a) or Rb, allows cells to bypass premature senescence that is induced by BS69 knockdown
17690110	In addition, we also found that the TWIST-mediated cellular senescence was regulated through its negative effect on p14(ARF) and subsequent suppression of MDM2/p53 and Chk1/2 DNA damage response pathways
17690110	Our results suggest that over-expression of TWIST results in down-regulation of p14(ARF), which leads to the impairment of DNA damage checkpoint in response to genotoxic stress
17671205	Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest
17664422	MYC inactivation was associated with prototypical markers of senescence, including acidic beta-gal staining, induction of p16INK4a, and p15INK4b expression
17664422	Osteosarcomas engineered to be deficient in p16INK4a or Rb exhibited impaired senescence and failed to exhibit sustained tumor regression upon MYC inactivation
17662938	Cellular senescence, a state of irreversible growth arrest, can be triggered by multiple mechanisms including telomere shortening, the epigenetic derepression of the INK4a/ARF locus, and DNA damage
17638879	The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence
17638879	This bypass was accompanied by epigenetic DNA methylation of the p16(INK4A) promoter and correspondingly a loss of expression of this tumor suppressor
17638879	Knockdown of p16(INK4A) cooperated with PAX3-FKHR to drive proliferation past senescence, whereas reintroduction of wild-type p16(INK4A) in post-senescent cells caused growth arrest
17638879	Thus, PAX3-FKHR acts in concert with loss of p16(INK4A) to promote inappropriate proliferation of skeletal muscle cells
17638879	This association between PAX3-FKHR expression and p16(INK4A) loss was seen in human ARMS tumor tissue, as both human rhabdomyosarcoma cell lines and tissue microarrays showed a trend toward down-regulation of p16(INK4A) protein in alveolar subsets
17638879	We surmise that the generation of the PAX3-FKHR fusion protein may require loss of p16(INK4A) to promote malignant proliferation of skeletal muscle cells as an early step in ARMS tumorigenesis
17634581	Replicative senescence due to telomere shortening can, for example, be induced by a dominant negative version of telomerase, premature senescence by the overexpression of oncogenic ras, or p16
17627613	The ectopic expression of ESE-3 resulted in retarded growth, up-regulation of p16(INK4a) but not of p21, and increased levels of SA-beta-gal activity
17627613	ESE-3 expression increased the activity of the p16(INK4a) promoter in a reporter assay, and recombinant ESE-3 protein bound to the Ets-binding sequences present in the promoter
17612587	Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers
17599058	Genetic cooperation between p21Cip1 and INK4 inhibitors in cellular senescence and tumor suppression
17599058	Some of these proteins, p21(Cip1), p16(INK4a) and p15(INK4b), are coexpressed in response to antiproliferative signals such as cellular senescence resulting in cell-cycle arrest
17599058	To understand the roles of these inhibitors and their synergistic effect, we have characterized the growth properties and senescent behavior of primary cells deficient in p21(Cip1) and expressing an endogenous Cdk4(R24C) (cyclin-dependent kinase) mutant (Cdk4(R24C) knock-in cells) insensitive to INK4 proteins
17599058	Inactivation of both p21(Cip1) and INK4 pathways strongly cooperate in suppressing cellular senescence in vitro
17599058	Moreover, mice double mutant in the INK4 and p21(Cip1) pathways (Cdk4(R24C); p21(Cip1)-null mice) display an increased incidence of specific sarcomas, suggesting a significant cooperation between these two families of cell-cycle inhibitors in senescence responses and tumor suppression in vivo
17578512	The retinoblastoma (RB)/p16(INK4a) pathway regulates senescence of human melanocytes in culture and oncogene-induced senescence of melanocytic nevi in vivo
17569790	Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion
17569790	The expression level of the p16INK4A gene was associated closely with the PD number of each strain (p =
17569790	Most of the p16INK4A-positive cells were Ki67-negative and senescence associated beta-galactosidase-positive, and the suppression of p16INK4A gene expression by small interfering RNA in senescent hMSCs reduced the number of senescent cells and endowed them with the ability to proliferate
17569790	Twenty-five of the 29 strains showed a steady gradual increase in the expression of p16INK4A
17569790	These results indicated p16INK4A to be a key factor in the regulation of hMSC growth, and, most importantly, careful monitoring of DNA methylation should be considered during the culture of hMSCs, particularly when a prolonged and extended propagation is required
17562874	In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence
17546053	The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence
17546053	We demonstrate that NPMc+ blocks the p19(Arf) (Arf) induction elicited by E1A
17546053	We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway
17532297	Because hMSCs were induced cellular senescence due to long-term culture, FGF-2 decreased the percentage of senescent cells and suppressed G1 cell growth arrest through the suppression of p21(Cip1), p53, and p16(INK4a) mRNA expression levels
17498290	Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry
17498290	RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A
17498290	In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A
17498290	Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-beta-gal staining, and a decrease in replicative potential
17498290	Importantly, there was a positive correlation between P16INK4A and matrix-degrading enzyme gene expression
17475325	Does p16ink4a expression increase with the number of cell doublings in normal and malignant lymphocytes
17475325	We analyzed to what extent the number of cell doublings may participate to p16(ink4a) expression in normal and malignant lymphocytes
17475325	Afterwards, in lymphocyte long-term cultures, the increase in p16(ink4a) followed the expression of features of cell ageing
17475325	These results support the hypothesis that (i) an increase in p16(ink4a) expression in normal lymphocytes is linked, in part, to the number of cell doublings before the occurrence of replicative senescence and (ii) this process is maintained in leukemic cell populations of numerous patients
17459456	A common variant of the p16(INK4a) genetic region is associated with physical function in older people
17459456	Deletion of the small p16(INK4a)/ARF/p15(INK4b) region occurs in many cancers
17459456	In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16(INK4a)/ARF locus and p15(INK4b)) was associated with reduced physical impairment
17459456	These findings require further replication, but provide the first direct evidence that the p16(INK4a)/ARF/p15(INK4b) genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations
17452980	Moreover, depletion of hAda3 by siRNA inhibited endogenous p53 acetylation and accumulation of p21cip1 in response to ectopic p14ARF
17452980	These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence
17447021	To investigate the effect of cell cycle inhibitor p14ARF on replicative senescence of human diploid cell, recombinant p19ARF eukaryotic expression vector was constructed and p19ARF gene was transfected into human diploid fibroblasts (WI-38 cells) by liposome-mediated transfection for overexpression
17376312	Posttranscriptional induction of p21Waf1 mediated by ectopic p16INK4 in human diploid fibroblast
17376312	BACKGROUND: Both p16(INK4) and p21(Waf1) are tumor suppressors with similar biological functions in the regulation of cellular senescence
17376312	This study was undertaken to determine the effects of p16(INK4) on the expression and functions of p21(Waf1)
17376312	METHODS: Human diploid fibroblast 2BS cells were stably transfected with sense (2BS/p16(INK4)), antisense p16(INK4) (2BS/asp16(INK4)) or empty vector (2BS/neo)
17376312	CONCLUSION: p16(INK4) may play an important role in the regulation of cellular senescence by modulating the p21(Waf1) protein level via the posttranscriptional mechanism
17344414	The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood
17343761	However, in human cells, once pRb is fully activated by p16INK4a, senescence cell cycle arrest becomes irreversible and is no longer revoked by subsequent inactivation of pRb, suggesting that p16INK4a/Rb-pathway activates an alternative mechanism to irreversibly block the cell cycle in human senescent cells
17297463	ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2
17297463	The INK4a/ARF locus, encoding two tumor suppressor proteins, p16(INK4a) and p14(ARF) (ARF), plays key roles in many cellular processes including cell proliferation, apoptosis, cellular senescence and differentiation
17297463	Inactivation of INK4a/ARF is one of the most frequent events during human cancer development
17297463	A body of evidence indicates that ARF also possesses growth suppression functions independent of p53, the mechanism of which is not well understood
17297463	In this study, we show that ARF disrupts MDM2-Rb interaction resulting in Rb accumulation
17297463	Wild-type ARF, but not ARF mutant defective in MDM2 interaction, stabilizes Rb and inhibits colony foci formation independent of p53
17297463	In addition, ablation of Rb impairs ARF function in growth suppression
17297463	Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development
17291294	Analysis of aortic tissue preparations from young and old Brown Norway rats showed that expression of senescence markers such as p16(INK4a) and senescence-associated beta-galactosidase activity are detected primarily in the old tissues
17291294	VSMC from p16(INK4a) knockout and control mice display similar levels of polyploid cells
17227869	Cdc42GAP-/- mouse embryonic fibroblasts and/or tissues display reduced population doubling, significantly dampened DNA damage repair activity after DNA-damaging agent treatment, accumulated genomic abnormalities, and induction of p53, p16Ink4a, p21Cip1, and senescence-associated beta-galactosidase expressions
17225865	BACKGROUND: p16(INK4a) tumor suppressor protein has been widely proposed to mediate entrance of the cells into the senescent stage
17183247	Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease
17183247	The cell cycle inhibitor p16(INK4A) (also known as cyclin-dependent kinase inhibitor 2A) is expressed in vivo in many tissues with age
17183247	The exposure of certain chronic stresses can trigger p16(INK4A) expression and a senescence-like phenotype
17183247	We studied whether p16(INK4A) expression is induced in glomerular disease (GD)
17183247	We performed p16(INK4A) immunostaining on 35 biopsies with GD, 12 tubulointerstitial nephritis (TIN), and 19 normal live donor kidneys at transplantation
17183247	Based on values for 42 normal kidneys, we calculated expected nuclear p16(INK4A) expression for age and compared the observed values in diseased kidneys to those expected for age
17183247	In GD, p16(INK4A) expression was strikingly increased in glomerular and interstitial cell nuclei compared to normals and TIN, and could not be attributed to age (P<0
17183247	By multivariate analyses, GD was independently associated with increased nuclear p16(INK4a) expression in glomeruli (P<0
17183247	The p16(INK4A) expression in glomerular and interstitial cell nuclei, and tubular cytoplasm was higher in kidneys with proteinuria and with atrophy/fibrosis (P<0
17183247	Older age was associated with increased nuclear p16(INK4a) expression in tubules (P=0
17183247	The p16(INK4a) staining in tubular cytoplasm was increased in both GD and TIN compared to normals (P<0
17183247	Thus, kidneys with GD display increased expression of senescence marker p16(INK4A) in glomerular and interstitial cell nuclei compared to kidneys with normal aging or TIN
17158953	The expression of N-terminally enhanced green fluorescent protein (EGFP)-tagged histone H1 induces premature senescence phenotypes, including increased levels of phosphorylated p53, p21, and hypophosphorylated Rb, and a decrease in the chromatin-bound endogenous histone H1 level but not in p16 level accumulation or SAHF formation
17151361	It regulates cellular senescence and proliferation of cells via the transcriptional repression of INK4a/ARF locus and other target genes
17145814	Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers
17145814	The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions
17116315	We show that dermal fibroblasts, displaying markers of senescence such as telomere damage, active checkpoint kinase ATM, high levels of heterochromatin proteins and elevated levels of p16, accumulate in skin biopsies from baboons with advancing age
17102614	We recently found that human fibroblasts or endothelial cells with genetically-engineered reduction of proto-oncogene c-Myc expression switched with an increased frequency to a senescent state by a telomere-independent mechanism involving the polycomb group repressor Bmi-1 and the cyclin-dependent kinase inhibitor p16(INK4a)
17098706	In senescent MEF cells, DNA methylation of p16INK4a 5'-regulatory region showed gradual reduction as cells aged
17098706	RT-PCR and Northern blot demonstrated that the expression of p16INK4a in transfected senescent cells was 12-16 times more than primary cells
17097049	In Atm-null testicular cells, differing from bone marrow cells of Atm-null mice, reactive oxygen species-mediated p16(Ink4a) activation does not occur in Atm-null premeiotic germ cells, which suggests the involvement of different signaling pathways from bone marrow defects
17034355	The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53
17028578	The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence
17028578	Here, we show that the p16(INK4a) /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cdelta (PKCdelta) in human senescent cells
17026941	The transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response
17026941	This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47
17026941	The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation
17026941	The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood
17026941	Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases
17026941	Indeed, RNA Helicase A might protect INK4a against methylation of CpG island
17026941	Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression
17026941	The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents
17016587	The characteristics of proliferation and metastasis were shown by PCNA (proliferating cell nuclear antigen), and nm23 and cell cycle-related genes, such as p16, p21, p53 and pRb, were analyzed by RT-PCR and immunohistochemistry
17016587	The cell cycle-related genes, such as p16, p21, p53 and pRb, were not detected in F6 cells, while the expression of hTRAP and BMI-1 was significantly higher
17015432	CPEB cannot stimulate senescence in MEFs lacking the tumor suppressors p53, p19ARF, or p16(INK4A); however, the mRNAs encoding these proteins are unlikely targets of CPEB since their expression is the same in wild-type and KO MEFs
16957735	Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
16957735	Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions
16957735	Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model
16957735	Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue
16951325	Strikingly, late passage T cells overexpressing telomerase accumulated the cyclin-dependent inhibitors p16Ink4a and p21Cip1 that have largely been associated with in vitro growth arrest
16951325	We conclude that alternative growth arrest mechanisms such as those mediated by p16Ink4a and p21Cip1 still remained intact and regulated the growth potential of cells independently of their telomere status
16936260	Cellular senescence of biliary epithelial cells with p16INK4a and p21WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis
16936260	We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence
16936260	In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16INK4a expression
16936260	In cultured biliary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression
16936260	A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence
16911562	The cell-cycle regulating gene, p16INK4A, encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an important role in cellular aging and in premature senescence
16911562	Although there is an age-dependent increase of p16INK4A expression in human fibroblast senescence in vitro, no data are available regarding the age dependency of p16INK4A in vivo
16911562	To determine whether p16INK4A expression in human skin correlates with donor age, p16INK4A expression was analyzed by immunohistochemistry as well as the expression of the p16INK4A repressor BMI1
16911562	In immunofluorescence co-expression studies, Ki67-positive cells were negative for p16INK4A and BMI1-expressing cells also stained negatively for Ki67
16911562	In conclusion, we provide for the first time evidence that p16INK4A expression directly correlates with chronological aging of human skin in vivo
16901784	HMGA proteins cooperate with the p16(INK4a) tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes
16888288	MAIN RESULTS: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers
16888288	They had also significantly higher percentages of endothelial cells positive for p16INK4a than the asymptomatic smokers and nonsmokers, and higher percentages of endothelial cells positive for p21CIP1/WAF1/Sdi1 than the asymptomatic nonsmokers
16888288	The level of p16INK4a expression was negatively correlated with the level of PCNA expression
16880792	Cellular senescence in naevi and immortalisation in melanoma: a role for p16
16880792	Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation
16880792	Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed
16880792	In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining
16880792	All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation)
16880792	Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi
16880792	This also provides a potential explanation of why p16 is a melanoma suppressor gene
16880208	Increased VEGF expression was specific to the senescent phenotype and increased whether senescence was induced by replicative exhaustion, overexpression of p16(Ink4a), or overexpression of oncogenic RAS
16869752	Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genes that are commonly deleted in cancer
16869752	Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentially reducing stem cell frequency and function
16840774	When we examined multiple exposures to CSE, we found that the cells had profound growth arrest, a flat and enlarged morphology, upregulated p16, and senescence-associated beta-galactosidase activity, which is consistent with a classic senescent phenotype
16799475	We detected positive staining of p16(INK4a) in 19% of the PIN, 25% of the low-grade carcinoma, and 43% of the high-grade carcinoma specimens but none in the normal prostate and nodular hyperplasia specimens
16799475	Expression of p14(ARF) revealed very high levels of expression in normal tissues (83%), nodular hyperplasia (88%), PIN (89%), and cancer cells (100%)
16799475	Because p16(INK4a)-positive cells were detected only in premalignant lesions and carcinomas but not in normal or benign tissues, p16(INK4a) may aid in the diagnosis of PIN and prostate cancer in difficult cases
16794190	VSMCs in fibrous caps expressed markers of senescence (senescence-associated beta-galactosidase [SAbetaG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels
16794190	VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB
16763167	We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart
16708569	In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions
16635496	Activation of the mitogen-activated protein kinase EKR and up-regulation of cyclin-dependent kinase inhibitor p16 were found in early stages of GolF treatment and were presumed to cause cell-cycle arrest and trigger premature senescence of HepG2 cells
16603702	Studies support a central role for Rb protein in controlling this process after it receives senescent signals from the p53 and p16 pathways
16569765	Here, we report that enduring AZT treatment of T-cell leukemia virus I-infected cells, in vitro and in vivo in ATL patients, results in inhibition of telomerase activity, progressive telomere shortening, and increased p14(ARF) expression
16567311	N-Myc promotes cell proliferation whereas Twist 1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway
16537449	Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a)
16537449	Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a)
16476774	Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy
16457693	The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action
16457693	CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects
16380648	We also studied changes in telomerase activity and the related senescence genes, such as p21 and p16
16288006	Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells
16288006	In MRT cell lines, reexpression of hSNF5 induces G1 cell cycle arrest, elevated p16INK4a, and activated replicative senescence markers, such as beta-galactosidase (beta-Gal) and plasminogen activator inhibitor-1
16288006	To compare the replicative senescence caused by hSNF5 in A204 cells to normal cellular senescence, we examined the activation of both p16INK4a and p21CIP/WAF1
16288006	Analogous to normal cellular senescence, both p16INK4a and p21CIP/WAF1 were up-regulated following hSNF5 restoration
16288006	Furthermore, we found that hSNF5 bound the p16INK4a and p21CIP/WAF1 promoters, suggesting that it directly regulates transcription of these genes
16288006	Using p16INK4a RNA interference, we showed its requirement for the replicative senescence caused by hSNF5 but not the growth arrest
16288006	Instead, p21CIP/WAF1 remained activated by hSNF5 in the absence of high p16INK4a expression, apparently causing the growth arrest in A204
16288006	Interestingly, we also found that, in the absence of p16INK4a, reexpression of hSNF5 also increased protein levels of a second cyclin-dependent kinase (CDK) inhibitor, p18INK4c
16254068	Compared with early-passage cells, the late-passage HPMC exhibited increased expression of p16INK4a but not of p21Cip1
16254068	These results demonstrate that early onset of senescence in omentum-derived HPMC may be associated with oxidative stress-induced upregulation of p16INK4a
16243918	Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53
16243918	When compared with native collagen, early passage HUVECs showed increased p53, p21(CIP1) (p21), and p16(INK4a) (p16) mRNA expression after exposure to GC
16243918	Twenty-four hours after transfection of p16, p21, and p53-enhanced green fluorescent protein (EGFP) recombinant plasmids, HUVECs entered G(1)-phase cell cycle arrest
16243918	Cotransfection of p16 and p21 showed no additive effect
16243918	Next, we suppressed endogenous p53, p21, p16, or retinoblastoma (Rb) gene expression through small interference RNA strategy and investigated their influence in p16- and p21-initiated endothelial cell senescence
16243918	Analysis indicated that suppression of p53 expression can abolish senescence induced by p16 overexpression
16243918	On the other hand, suppression of Rb eliminated senescence initiated by either p16 or p21 overexpression
16243918	In summary, the p53/p21 pathway is mainly responsible for GC-induced apoptosis, but the coordinated activation of the p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence through a Rb-dependent mechanism
16229875	The cyclin dependent kinase inhibitors p21 and p16(INK4a) have been shown to execute and maintain the cell cycle arrest in senescence but the nature of the signals that cause upregulation of these inhibitors in senescent cells are only now starting to be discovered
16229875	Here we will review the current literature that leads us to propose a model how independent signals activate distinct signaling pathways to regulate p21 and p16(INK4a) levels in senescent cells
16150936	In addition, LKS+ HSCs from irradiated mice exhibited an increased expression of the 2 commonly used biomarkers of cellular senescence, p16(Ink4a) and SA-beta-gal
16150936	Of interest, the induction of HSC senescence was associated with a prolonged elevation of p21(Cip1/Waf1), p19(Arf), and p16(Ink4a) mRNA expression, while the expression of p27(Kip1) and p18(Ink4c) mRNA was not increased following TBI
16150936	This suggests that p21(Cip1/Waf1), p19(Arf), and p16(Ink4a) may play an important role in IR-induced senescence in HSCs
16109412	A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells
16107878	Senescence is an irreversible form of G1 arrest that requires the p19ARF/p53 and p16INK4a/pRB pathways and may suppress tumorigenesis in vivo
15888044	Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney
15888044	Since expression of p16(INK4a), a cell cycle inhibitor associated with somatic cell senescence in vitro, is induced in aged kidney, we studied whether kidneys with dysfunction and TA/IF manifested increased p16(INK4a) expression
15888044	We performed p16(INK4a) immunostaining on transplanted kidneys and native kidneys with chronic renal diseases
15888044	At implantation, transplants manifested little TA/IF, and nuclear p16(INK4a) immunostaining was consistent with age
15888044	However, transplants biopsied for abnormal function displaying TA/IF showed strong nuclear and cytoplasmic p16(INK4a) staining, beyond the amount predicted for age
15888044	Both atrophic and non-atrophic nephrons displayed increased p16(INK4a), suggesting that it was not simply a feature of atrophy
15888044	Epithelial p16(INK4a) staining was not increased in transplants with good function, but was increased in diseased native kidneys
15888044	The finding of increased p16(INK4a) expression in renal transplants and diseased kidneys with TA/IF and impaired function supports the concept that some cell senescence changes that accompany aging are also induced by injury and disease stresses
15885198	These barriers are regulated by telomere shortening and by the p16(INK4a)/Rb and p53 tumour suppressor pathways
15821417	So far, p16 remains the best marker of chronological age in the kidney, and can be considered as an indicator of premature senescence caused by stresses or disease
15811424	In this study, altered hMSCs were verified to be senescent by their senescence-associated beta-galactosidase (SA-beta-gal) activity and the increased expression of cell cycle regulating proteins (p16(INK4a), p21(Waf1) and p53)
15781639	The INK4a and ARF genes found at the CDKN2A locus are key effectors of cellular senescence that is believed to act as a powerful anticancer mechanism
15781639	Accordingly, mutations in these genes are present in a wide variety of spontaneous human cancers and CDKN2A germ line mutations are found in familial melanoma
15781639	Overexpression of Tbx2 and the related factor Tbx3, which is also overexpressed in breast cancer and melanomas, can suppress senescence in defined experimental systems through repression of ARF expression
15781639	This is a particularly important question because the loss of CDKN2A in many human cancers would, in principle, bypass the requirement for Tbx2/3-mediated repression of ARF in suppressing senescence
15685690	Biliary epithelial cells in small bile ducts in primary biliary cirrhosis, especially those in patients presenting with chronic non-suppurative cholangitis, frequently expressed senescence-associated beta-galactosidase, and senescence-associated p16(INK4) and p21(WAF1/CIP)
15659210	Levels of the tumor suppressor protein p16INK4A increased in all senescent cells whether telomerase-positive or -negative
15658102	Each of these nestin-expressing immortalized cell lines harbored a common homozygous deletion spanning the INK4a/ARF locus and was unable to differentiate into neural lineages after exposure to specific in vitro stimuli
15657429	The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally
15657429	Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7
15647378	Immortalization of human fetal cells: the life span of umbilical cord blood-derived cells can be prolonged without manipulating p16INK4a/RB braking pathway
15647378	The p16INK4a/RB braking pathway leading to senescence can be inhibited by introduction of Bmi-1, a polycomb-group gene, and human papillomavirus type 16 E7, but the extension of the life span of the UCBMSCs with hTERT did not require inhibition of the p16INK4a/RB pathway
15610763	TGF-beta1 induced neither expression of senescence-associated markers nor genes involved in terminal growth arrest, such as senescence-associated beta-galactosidase and cyclin-dependent kinase (cdk) inhibitors p16(Ink4A) and p21(Cip1) but increased p15(Ink4B) protein expression
15520862	Ink4a/Arf expression is a biomarker of aging
15520862	The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence
15520862	To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging
15520862	We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors
15520862	The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs
15520862	Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules
15520862	These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging
15520854	The products of the INK4a/ARF locus--p16INK4a and ARF--arrest cell proliferation at the senescence stage by exerting their effects on retinoblastoma protein- and p53-mediated responsive pathways
15460900	The p16INK4a tumor suppressor protein functions as an inhibitor of CDK4 and CDK6, the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB
15460900	Thus, p16INK4a has the capacity to arrest cells in the G1-phase of the cell cycle and its probable physiological role is in the implementation of irreversible growth arrest termed cellular senescence
15460900	In contrast to normal cells, the function of the p16INK4a gene or its downstream mediators is frequently deregulated in many types of human cancers, illustrating the importance of cellular senescence in tumor suppression
15377661	This was followed by sequential induction of p53, p21, and p16
15247028	This was associated with high levels of the CdkIs p16 and p21
15247028	Similarly, presenescent WS fibroblasts expressing the E6 and/or E7 oncoproteins bypassed M1 and ultimately reached a second proliferative life span barrier, which strongly resembled the second life span barriers found in normal cells for growth dynamics, cellular morphology, and expression of p16 and p21
15242773	The induction of HDF senescence was associated with an activation of p53, increased expression of p21Cip1/WAF1, and hypophosphorylation of retinoblastoma protein (Rb), while no changes in the expression of p16Ink4a, p27Kip1, and p14Arf were observed
15153805	Moreover, extended passaging of normal fibroblasts leads to increased levels of the cyclin dependent kinase inhibitor p16 and sensitizes cells to senescence induced by RAS
15149599	Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)
15149599	These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells
15138605	Since p16INK4a is also a key element controlling cellular senescence and other functions, we hypothesized that p16INK4a induced tumor suppression may not be limited to the inhibition of cdks
15138605	Stable expression of p16INK4a suppressed the malignant phenotype in MCF-7 cells, including cell proliferation, anchorage-independent growth, G1/G0 cell cycle arrest, and the blockage of pRB phosphorylation
15138605	In addition, expression of p16INK4a suppressed telomerase activity and restored the telomere shortening process, and decreased cell DNA repair ability and sensitized cells to the DNA damage reagent
15138605	Our data suggest that the wild-type p16INK4a plays an important role in suppression of tumor malignancy, not only by inhibiting cell proliferation through cell cycle arrest, but also by inhibiting other cellular controlling mechanisms, such as telomerase activity and DNA repair capacity
15138269	Regulation of cellular senescence and p16(INK4a) expression by Id1 and E47 proteins in human diploid fibroblast
15138269	Id1, a member of Id family of helix-loop-helix transcriptional regulatory proteins, is implicated in cellular senescence by repressing p16(INK4a) expression, but the mechanisms and cellular effects in human diploid fibroblasts remain unknown
15138269	Here we analyzed the patterns of p16(INK4a) and Id1 expression during the lifespan of 2BS cells and presented the inverse correlation between these two proteins
15138269	Immunoprecipitation assays demonstrated the presence of endogenous interaction of Id1 and E47 proteins that was strong in young 2BS cells and weakened during replicative senescence and, thereby, influenced the transcription activation of p16(INK4a) by E47
15138269	Furthermore, we found that E47 protein could bind to the E-box-containing region in p16(INK4a) promoter in senescent cells by chromatin immunoprecipitation analyses, suggesting that E47 is indeed ultimately involved in the regulation of p16(INK4a) transcription in vivo
15138269	Silencing Id1 expression in young cells by RNA interference induced an increased p16(INK4a) level and premature cellular senescence, whereas silencing E47 expression inhibited the expression of p16(INK4a) and delayed the onset of senescent phenotype
15138269	The present study demonstrated not only the capacity of Id1 to regulate p16(INK4a) gene expression by E47, but also the phenotypic consequence of the regulation on cellular senescence, moreover, raised the possibility of Id1-specific gene silencing for human cancer therapy
15111320	The Ishikawa cell line, with stable or tetracycline-regulated expression of mutant beta-catenin, showed an increase in expression levels of cyclin D1, p14ARF, p53, and p21WAF1 but not PML, and activation of beta-catenin-TCF4-mediated transcription determined with TOP/FOP constructs
15111320	Moreover, overexpressed beta-catenin could activate transcription from p14ARF and cyclin D1 promoters, in a TCF4-dependent manner
15064751	The Id1 is a basic helix-loop-helix (bHLH) protein and a negative transcriptional regulator of p16(INK4a)
14980702	Simultaneous induction of p16(INK4a) and p53 was detected in G6PD-deficient but not in normal fibroblasts during H(2)O(2)-induced senescence
14726476	Gene products implicated in growth arrest and senescence, such as p27Kip1, p53, p16INK4a, and p19ARF, were detected in myocytes of young WT mice, and their expression increased with age
14717921	Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney
14717921	Among the candidate genes surveyed, the cell cycle regulator p16INK4a emerged with the strongest association with renal aging for both mRNA and protein expression
14717921	Proliferation as measured by Ki-67 expression was inversely correlated with p16INK4a expression, compatible with a role for p16INK4a as an irreversible cell cycle inhibitor
14717921	P16INK4a emerged with the most consistent correlations with age and histologic changes and inversely correlated with cell replication
14677632	Gamma irradiation, DNA-damaging drugs, expression of p14(ARF) or oncogenic Ras, and replicative exhaustion all resulted in elevated EYFP expression, demonstrating its proper control by physiological signalling circuits
14604992	P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells
14604992	Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis
14604992	Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex
14604992	Three lines of evidence established that p16(INK4a) is an essential effector of hSNF5-induced cell cycle arrest
14604992	1) Overexpression of p16(INK4a) mimics the effect of hSNF5 induction and leads to cellular senescence
14604992	3) Inhibition of p16(INK4a) activation by siRNA blocks hSNF5-mediated cellular senescence
14604992	Collectively, these results indicate that in human MRT cells, the p16(INK4a)/pRb, rather than the p14(ARF)/p53 pathway, mediates hSNF5-induced cellular senescence
14580871	TGF-beta-treated prostate epithelial cells neither showed terminal growth arrest nor induction of important senescence-relevant genes, such as p16(INK4A), IFI-6-16, IGFBP-3 or Dkk-3
14500376	Moreover, these surviving cells expressed an increased level of senescence-associated beta-galactosidase, p16(Ink4a), and p19(Arf)
12958145	Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16INK4a positive primitive cells and myocytes, and no structural damage
12958145	Cell death markedly increased and occurred only in cells expressing p16INK4a that had significant telomeric shortening
12958145	Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16INK4a labeling
12943534	Although it was shown that activation of the senescence programme involves the up-regulation of cell-cycle regulators such as the inhibitors of cyclin-dependent kinases p16INK4A and p21CIP-1, the mechanisms underlying the senescence response remain to be resolved
12912919	Reversal of human cellular senescence: roles of the p53 and p16 pathways
12912919	We show that, depending on expression of the pRB regulator p16, replicative senescence is not necessarily irreversible
12912919	However, cells with low levels of p16 at senescence resumed robust growth upon p53 inactivation, and limited growth upon expression of oncogenic RAS
12912919	In contrast, cells with high levels of p16 at senescence failed to proliferate upon p53 inactivation or RAS expression, although they re-entered the cell cycle without growth after pRB inactivation
12912919	However, p16 provides a dominant second barrier to the unlimited growth of human cells
12902982	Activation of E2F1 induced p14ARF mRNA and protein levels
12883667	Adenoviral p16/CDKN2 gene transfer to malignant glioma: role of p16 in growth, invasion, and senescence
12883667	In gliomas, a high frequency of homozygous p16 gene deletions have been demonstrated, which are believed to be linked with malignant progression
12883667	The aim of this study was to assess the role of p16 in growth, invasion, and senescence
12883667	Taken together these data strongly suggest that the anti-cancer effect of p16 is modulated by p16-mediated cell cycle arrest and by the induction of senescence
12877804	METHODS: Using a PI3Ks specific inhibitor, LY294002, cell cycle, apoptosis, proliferation, senescence association beta-galactosidase staining as well as senescence association CKIs, p16(INK4) and p21(Cip1) protein expressions were all measured in the low passages of 2BS cells
12877804	In addition, LY294002 could induce time-course expressions of p16(INK4) and p21(Cip1) in 2BS cell lines
12877804	Two senescence associated CKIs, p16(INK4) and p21(Cip1), might be involved in this senescence phenotype proceeding in 2BS cell lines
12789281	Based on the evidence including growth and survival kinetics of human and mouse melanocytes carrying germline deficiencies in the INK4A sequence, it is suggested that an 'M0' or p16/RB-dependent form of senescence may be particularly important in melanocytes
12759390	BACKGROUND: The melanoma susceptibility locus cyclin-dependent kinase inhibitor 2A encodes two unrelated cell growth inhibitors, p16 and alternative reading frame (ARF)
12759390	The p16 coding sequence is more often mutated in melanoma families than is the ARF sequence
12759390	To investigate the role of p16 in melanocytes, we assessed aspects of growth, apoptosis, and immortalization in melanocytes cultured from two melanoma patients, both of whom had two inactive p16 alleles but functional ARF
12759390	CONCLUSION: Normal senescence in human melanocytes requires p16 activity
12759390	These findings provide some basis for the role of p16 in melanoma susceptibility
12753300	Expression of mRNA for p16INK4a, a characteristic senescence gene in vitro, was undetectable in most young rats but rose 27 fold during growth and a further 72-fold during aging
12729792	The bypass of the growth arrest and the acquisition of long-term growth properties could be explained by the loss of p16(INK4a) expression, the ARF/p53 pathway not being altered
12651622	It is known that shortened telomeres can activate cell cycle regulators, such as p21 and p16
12651622	Accordingly, all cases showed a transient p21 increase, with a maximum at day 7 and a sustained expression of p16
12651622	In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts
12615976	This was associated with hypophosphorylated pRb and high levels of p16(Ink4a) and p21(Waf1)
12507899	Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes
12507899	Induction of p14(ARF) on confluency occurred with low E2F-1 levels
12507899	Addition of MAPK inhibitor blocked cytokine and TPA-induced p16 expression
12414954	At the molecular level, cells infected by HCMV, beside the accumulation of large amounts of the cell cycle regulators p53 and pRb, the latter in its hyperphosphorylated form, display a strong induction of the cyclin-dependent kinase inhibitor (cdki) p16(INK4a), a direct effector of the senescence phenotype in fibroblasts, and a decrease of the cdki p21(CIP1/WAF)
12414954	When baculovirus vectors expressing HCMV IE1-72 or IE2-86 proteins were inoculated into fibroblasts, the increase of p16(INK4a) (observed predominantly with IE2-86) was similar to that observed with the whole virus, as was the induction of SA-beta-Gal activity, suggesting that the viral IE2 gene leads infected cells into senescence
12414954	Altogether our results demonstrate for the first time that HCMV, after arresting the cell cycle and inhibiting apoptosis, triggers the cellular senescence program, probably through the p16(INK4a) and p53 pathways
12414655	The tumor suppressor genes p16(INK4A), pRb, and p53 have been implicated in the induction of cellular senescence
12392077	Induction of p16/INK4a gene expression and cellular senescence by toyocamycin
12392077	We constructed an assay system of a luciferase reporter with p16/lNK4a gene transcriptional regulatory domain to identify p16-inducing substances, and found toyocamycin to induce gene expression from the screening of culture fluids of Streptomyces
12392077	Toyocamycin is a nucleoside analog, and it increased the p16 mRNA level in human normal fibroblasts or synovial cells as assessed by Northern blot hybridization or real time RT-PCR
12392077	The transcriptional regulatory regions of human p16 gene that were responsible for the induction were analyzed using deletion mutants of the transcriptional regulatory region of p16 linked to the luciferase gene
12392077	The DNA fragment -111 to +1 bp from the cap site was sufficient to drive toyocamycin-activated transcription of p16/luciferase reporter
12370286	Extended passage, telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16
12209876	Modulation of the expression of p16INK4a and p14ARF by hnRNP A1 and A2 RNA binding proteins: implications for cellular senescence
12209876	In this study, we tested whether overexpression of either protein could modulate the mRNA isoforms of the INK4a locus, specifically p14(ARF) and p16(INK4a)
12209876	Both INK4a mRNA isoforms have been shown to be growth suppressors and deletions of this locus allow cells to escape cellular senescence
12209876	We have found that increasing the ratio of either hnRNP A1 or A2 over that of splicing factor SF2/ASF results in the preferential generation of the p14(ARF) isoform
12209876	Overexpression of A1 or A2 RNA binding proteins also appear to increase the steady state mRNA levels of both isoforms, suggesting that in addition to alternative splicing, A1 and A2 may effect p14(ARF) and p16(INK4a) mRNA stability
12209876	A constitutive decrease in the ratio of hnRNP A1 or A2 to SF2/ASF in senescent fibroblasts is typically accompanied by an increase in the level of p16(INK4a) isoform
12177246	These results demonstrate the importance of Id-1 in endothelial cell proliferation and indicate that Id-1 represses p16 expression, resulting in delayed senescence
12100489	The three genes so far associated with familial melanoma susceptibility--INK4A, CDK4 and ARF, are all implicated in the molecular pathways controlling cell senescence
12100489	Key molecular effectors in melanocyte senescence appear to include some in common with other cell types - telomere attrition and the p16/RB pathway, and one that is not commonly mentioned in this connection, the cAMP signalling pathway that also regulates melanocyte differentiation
12091906	The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia
12091906	We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO
12091906	AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types
12091906	In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence
12091906	Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter
12091906	In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation
12091906	Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias
12051701	Fibroblasts treated with pyruvate undergo a rapid growth arrest accompanied by elevated levels of the cell-cycle regulatory molecules p53, p21, and p16
12015983	A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy
12015983	We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a)
12015983	Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo
12015983	Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage
11995925	Induction of p16INK4a transcription and of cellular senescence by aclacinomycin-derivatives and cardiac glycosides
11995925	Stable transformants of Saos-2 cells that contain the luciferase reporter gene under the control of the human p16INK4a transcriptional regulatory region were established, and were used to identify growth-inhibiting substances from culture broths of actinomycetes and extracts of plants
11980715	All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16
11971980	Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway
11904317	BACKGROUND: The Ink4a-Arf tumor suppressor locus encodes two growth inhibitors, p16 and Arf, both of which are also implicated as effectors in cellular senescence
11904317	Retroviral vectors containing normal p16 and Arf complementary DNAs were used to restore expression of these genes in Ink4a-Arf(-/-) melanocytes
11904317	All of six spontaneously immortalized melanocyte or melanocyte precursor lines from Ink4a-Arf(+/+) mice lacked p16 protein expression, although most retained Arf protein expression
11904317	After restoration of p16 but not Arf expression, Ink4a-Arf(-/-) melanocytes stopped growing, became highly melanized, and expressed acidic beta-galactosidase
11904317	By contrast, restoration of Arf but not p16 expression led to cell death without evidence of senescence
11904317	CONCLUSION: Normal mouse melanocyte senescence and associated pigmentation require both copies of Ink4a-Arf and appear to depend more on p16 than on Arf function
11904317	Mutations of the INK4A-ARF locus may favor tumorigenesis from melanocytes by impairing senescence, cell differentiation, and (where ARF is disrupted) cell death
11795494	Interestingly, p16 was upregulated whenever T antigen is overexpressed
11781834	Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures
11781834	Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells
11756559	Mutations in CDK4 and its key kinase inhibitor p16(INK4a) have been implicated in the genesis and progression of familial human melanoma
11756559	The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16(INK4a)
11707927	Recent studies have shown that senescence can also be induced independently of a PD level by various factors; this premature senescence also appears to involve the activity of p53 and/or p16INK4
11695244	Over-expression of CDKIs p15INK4b, p16INK4a and p21CIP1/WAF1 genes mediate growth arrest in human osteosarcoma cell lines
11695244	Transient expression of various CDKIs (p15INK4b, p16INK4a and p21CIP1/WAF1) in KHOS cells resulted in growth arrest and the cells failed to enter the S-phase of the cell cycle as shown by a DNA synthesis inhibition assay
11695244	In addition, stable transfection of p21CIP1/WAF1 and p16INK4a genes in two osteosarcoma cell lines (KHOS and U2-OS cells) showed that p21CIP1/WAF1 was able to repress the immortal phenotype in both cell lines, whereas temporary over-expression of p16INK4a reversibly inhibited the cell growth
11642719	P16 expression was widespread with most of Hassall's corpuscles being p16-positive
11606567	Senescence delay of human diploid fibroblast induced by anti-sense p16INK4a expression
11606567	To further explore the involvement of p16(INK4a) in replicative senescence, we constructed a retroviral vector containing antisense p16(INK4a), pDOR-ASp16, and introduced it into early passages of human diploid fibroblasts
11606567	The introduction of this construct significantly suppressed the expression of wild-type p16(INK4a)
11606567	These data not only strongly support a role for p16(INK4a) in replicative senescence but also raise the possibility of using the antisense p16(INK4a) therapeutically
11602203	In addition, senescence is associated with increased binding of the cyclin-dependent kinase inhibitor (CDK-I) p16(INK4a) to CDK4, down-regulation of cyclin E protein levels (and consequent loss of cyclin E/CDK2 activity), underphosphorylation of the retinoblastoma protein RB and subsequent increased levels of E2F4-RB repressive complexes
11602203	Cyclin E, p21(Waf-1) and p27(Kip-1) are also elevated in many primary melanomas, whereas p16(INK4a) is mutated or deleted in many invasive and metastatic melanomas
11598130	Characterization of regulatory elements on the promoter region of p16(INK4a) that contribute to overexpression of p16 in senescent fibroblasts
11598130	Cyclin-dependent kinase inhibitor p16(INK4a) is implicated in replicative senescence, cell immortalization, and tumor generation
11598130	We used the enhanced green fluorescent protein reporter system to scan regulatory elements in the upstream region of p16(INK4a)
11598130	The results of 5'-deletion studies indicated that the transcription regulatory elements contributing to overexpression of p16(INK4a) in senescent cells were located in the region of the p16(INK4a) promoter from -622 to -280 bp
11598130	According to the results of in vitro DNase I footprinting, EMSA, and Southwestern blotting, we found a novel negative regulatory element, the INK4a transcription silence element (ITSE), at -491 to -485 bp of the p16(INK4a) promoter
11598130	A 24-kDa protein that was highly expressed in young cells may inhibit the expression of p16(INK4a) by interacting with the ITSE
11598130	The activity of the p16(INK4a) promoter increased significantly in young cells when the ITSE was deleted
11598130	The GC-rich region of the p16(INK4a) promoter from -466 to -451 was a positive transcription regulatory element
11598130	4% loss of p16(INK4a) promoter activity in senescent cells, and the promoter activity decreased by 41
11593017	In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14(ARF), or hydrogen peroxide
11568971	No p16(Ink4a)/p19(Arf) alterations, such as deletion, mutations, or hypermethylation, were detected in the primary HT cells, although most cell lines derived from either normal or HT cell colonies lost p16(Ink4a) or p19(Arf) expression owing to hypermethylation or homozygous deletion of p16(Ink4a)/p19(Arf)
11427735	Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a
11427735	Our data provide, to our knowledge, the first genetic evidence for a role for Id1 as an inhibitor of cellular senescence and suggest that Id1 functions to delay cellular senescence through repression of p16/Ink4a
11407594	The INK4A/ARF locus: role in cell cycle control and apoptosis and implications for glioma growth
11407594	The unique INK4A/ARF locus at chromosome 9p21 encodes two distinct proteins that intimately link the pRB and p53 tumour suppressor pathways
11407594	The frequent mutation or deletion of INK4A/ARF in human tumours as well as the occurence of tumours in the murine knockout models have identified both p16 and ARF as bona fide tumour suppressors
11389930	In addition, at the end of their lifespans, the T cell clones did not display the CKI phenotype reported for senescent cells (an increase in p16 and p21 levels)
11302695	Failure of telomere shortening correlated with an inability to elevate p16 protein or mRNA in H(2)O(2)-treated cells
11234019	Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence
11234019	The p16INK4a cyclin-dependent kinase inhibitor is implicated in replicative senescence, the state of permanent growth arrest provoked by cumulative cell divisions or as a response to constitutive Ras-Raf-MEK signalling in somatic cells
11234019	Some contribution to senescence presumably underlies the importance of p16INK4a as a tumour suppressor but the mechanisms regulating its expression in these different contexts remain unknown
11234019	Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts
11234019	The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref
11234019	In senescent cells, where the Ets2 levels and MEK signalling decline, the marked increase in p16INK4a expression is consistent with the reciprocal reduction of Id1 and accumulation of Ets1
11208819	K-ras and p16 aberrations confer poor prognosis in human colorectal cancer
11208819	At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways
11208819	PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas
11208819	RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases
11208819	K-ras and p16 alterations were independent genetic events
11208819	Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant
11208819	Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras
11208819	Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis
11208819	CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer
11103932	We investigated the mechanism of cell cycle arrest at senescence in human mammary epithelial cells (HMECs) that have undergone a period of 'self-selection', and as a consequence exhibit diminished p16INK4A levels
11063935	The role of telomere maintenance in immortalization and the roles of p16(INK4A), p19(ARF), p53 and other genes in senescence are being further elucidated
11051194	Immunoblotting analysis of p16 protein recognized previously as a marker of senescent T cells, showed its highest and transient expression in presenescent cells
10978678	In addition, we determined the levels of cyclin-dependent kinase inhibitors, p21(Waf1) and p16(INK4a), and the p53 tumor suppressor in order to monitor its effect on cell cycle and stress responses
10978678	We observed a great induction of both p53 and p21(Waf1), but not of p16(INK4a) in the premature senescent cells
10961388	The hydroxyurea-treated cells showed positive senescence associated-beta-galactosidase staining, a senescence index, and the accumulation of cdk (cyclin dependent kinase) inhibitors, such as p16INK4a, p21Waf1, and p27Kip1, implicated in cellular senescence
10958672	Irreversible G(1) arrest in senescent human fibroblasts is mediated by two inhibitors of cyclin-dependent kinases (Cdks), p21(Cip1/SDI1/WAF1) and p16(Ink4A)
10958672	At the end of lifespan, terminal-passage E6 cells exhibited several aspects of the senescent phenotype and accumulated unphosphorylated pRb and p16
10911952	By inducing premature senescence with a pulse treatment of H2O2, we can study the role of the cell cycle checkpoint proteins p53, p21, p16 and Rb in gaining each feature of senescence
10911949	Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1
10911949	In these cells, senescence is associated with increased binding of p16INK4a to CDK4 and loss of E2F-binding activity
10911949	Here we demonstrate that in melanocytes derived from dark-skinned individuals, CT-induced melanogenesis is associated with accumulation of the tumor suppressor p16INK4a, underphosphorylated retinoblastoma protein (pRb), downregulation of cyclin E, decreased expression of E2F1, and loss of E2F-regulated S-phase gene expression
10911949	This delayed senescence may result from reduced association of p16 with CDK4, reduced levels of underphosphorylated pRb, and steady levels of cyclin E and E2F1
10911949	Because cyclin E-CDK2 inhibition is required for p16-mediated growth suppression, upregulation of p16 and downregulation of cyclin E appear essential for maintenance of terminal growth and senescence
10856888	Our studies, including analyses of the expression of senescence-associated beta-galactosidase, p16(INK4a) levels, and telomere lengths, indicate that cellular senescence is responsible for limiting the number of cell divisions that human beta-cells can undergo
10851091	Assembly and activity of the proto-oncogenic cyclin D/CDK4(6) complexes, the major driving force of G1 phase progression, is negatively regulated by a family of INK4 CDK inhibitors p16INK4a, p15INK4b, p18INK4c, and p19INK4d
10851091	These results highlight unexpected differences among the INK4 inhibitors, and suggest how p19INK4d may help regulate the rate of cyclin D/CDK4(6) complex formation, and thereby timely progression through the mammalian cell division cycle
10832053	Cyclin-dependent kinase inhibitors p16(INK4a), p21(Cip1), and p27(Kip1) are regarded as key effectors of cellular senescence
10832053	In this review, we describe three senescence-inducing pathways involving these inhibitors, namely, the p16(INK4a)/Rb pathway, the p19(ARF)/p53/p21(Cip1) pathway, and the PTEN/p27(Kip1) pathway
10803461	LMP1 of Epstein-Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression
10803461	It further suppresses the senescence-associated induction of p16INK4a, commonly believed to be a key regulator of replicative senescence
10803461	In addition, LMP1 was shown to prevent premature senescence provoked by oncogenic ras in mouse embryonic fibroblasts, and to inhibit the oncogene ras-mediated induction of p16INK4a and p21WAF1
10803461	Moreover, LMP1 is capable of suppressing the p16INK4a promoter in REF52 and Saos-2 cells in a promoter reporter assay
10803461	Our findings suggest that with the expression of p16INK4a and replicative senescence being suppressed, LMP1 may play a key role in Epstein-Barr virus-associated proliferative diseases, and it may further contribute to cancer development by preventing premature senescence induced by mitogenic oncogenes
10766342	Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence
10766342	As alterations in tumor-suppressor gene p16 are common in prostate cancer, one novel approach is gene therapy using a replication-deficient, E1/E3-deleted adenovirus type 5 containing a p16 under the control of a truncated Rous sarcoma virus promoter (AdRSVp16)
10766342	In vitro, PC-3 cells that had been stably transfected with p16 expression vector under the control of an inducible promoter had a 70% reduction in cell number compared with the parental and control vector-transfected PC-3 cells
10733143	CDKN2 is a tumor suppressor gene on chromosome 9p21
10733143	It encodes a nuclear protein, p16, which inhibits the D-type cyclin/cyclin-dependent kinase complexes that phosphorylate the retinoblastoma protein, thus blocking cell cycle progression through G1
10733143	The purpose of this study was to determine whether nuclear p16 expression is altered during the senescence of human pharyngeal epithelial cells (HPECs) m vitro
10733143	METHODS: An immunocytochemical study was performed to examine a panel of cultured HPECs with a finite lifespan for the nuclear p16 expression
10733143	RESULTS: Nuclear p16 was undetectable when HPECs were initially cultured in serum-free low-calcium medium
10733143	However, nuclear p16 was clearly detected when the cultured HPECs exhibited beta-galactosidase activity in the same medium
10733143	CONCLUSION: These results suggest that immunocytochemically detectable amounts of nuclear p16 are associated with senescence of HPECs in vitro
10585280	Activation of a cAMP pathway and induction of melanogenesis correlate with association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and premature senescence of human melanocytes
10585280	Here we present evidence that activation of a cAMP pathway correlates with multiple cellular changes in these cells: (1) increased expression of the transcription factor microphthalmia; (2) increased melanogenesis; (3) increased association of the cyclin-dependent kinase inhibitors (CDK-Is) p27(KIP1) and p16(INK4) with CDK2 and CDK4, respectively; (4) failure to phosphorylate the retinoblastoma protein (pRB); (5) decreased expression of E2F1, E2F2, and E2F4 proteins; (6) loss of E2F DNA-binding activity; and (7) phenotypic changes characteristic of senescent cells
10585273	Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: roles of p16, p21, and cyclin D1
10585273	Thus, one of the underlying molecular events involved in replicative senescence is the impaired activation of Cdk4 and Cdk2 due to increased binding of p16 to Cdk4 and increased association of Cdk2 with cyclin D1 and p21
10578056	Human cell lines lacking functional p21(wafl/sdi-1), p16(ink4a), or p53 behaved similarly
10578056	The protein levels of p16(ink4a) and p53 did not change uniformly, while the level of p21(wafl/sdi-1) was increased by varying degrees in positive cell lines
10537318	This lack of cdk activity and arrest in the G1 phase of the cell cycle is likely attributable to the induction upon senescence of the G1-S cdk/cyclin inhibitors p21 (WAF1/CIP1/Sdi) and p16INK4
10496532	Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues
10496532	Despite its importance in human neoplasia, the normal pattern of p16 expression remains largely unknown
10496532	Therefore, we analyzed the immunohistochemical localization of p16 in all human organs and demonstrated that cellular p16 expression is highly selective
10496532	Within each tissue, however, p16 expression does not correlate with cellular proliferation or maturation
10496532	In infants, p16 staining was limited to thymic Hassall's corpuscles, occasional thymic lymphocytes, and only rare pancreatic epithelial cells
10496532	Therefore, increased expression of p16 in adult tissues, as in mouse tissues, may reflect a role of p16 in cellular senescence
10496532	Restriction of p16 expression in infants to the thymus, the only organ committed to early senescence, is also consistent with such a role
10496532	Documentation of the pattern of p16 expression in normal tissues will contribute to our understanding of the normal function of this protein and to interpretation of potentially altered p16 expression in human tumors
10341711	Other inhibitory pathways are also activated (possibly by additional clocks), including the TSG p16INK4a and the less well-defined complementation group genes
10082130	Possible involvement of p21 but not of p16 or p53 in keratinocyte senescence
10082130	It has been reported that p21, p53, and p16 affect the cell cycle and cell senescence
10082130	To investigate the roles of p21, p53, and p16 in the cellular senescence of the cultured keratinocytes, we quantitatively analyzed p21, p53, and p16 levels of keratinocyte strains with different life spans by Western blot with Fluorol mager
10082130	The short life-span strains exhibited a significant increase in p16 levels in the senescent phase (eighth or tenth passage)
10082130	However, in two long life-span strains, p16 levels were increased in the nonsenescent phase (eighth passage) but then declined as the cells reached senescence (twenty-seventh passage)
10082130	Therefore, induction of p16 appeared not to be associated with senescence in long life-span strains
10082130	In conclusion, p21 but not p16 or p53 may play roles in keratinocyte senescence
10022898	Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts
10022898	Furthermore, the senescent-cell-cycle arrest occurs prior to the accumulation of the Cdk4-Cdk6 inhibitor p16(Ink4a), suggesting that p21 may be sufficient for this event
10022898	Accordingly, cyclin D1-associated phosphorylation of pRb at Ser-780 is lacking even in newly senescent fibroblasts that have a low amount of p16
10022898	Moreover, even in the late stage of senescence when p16 is high, cyclin D1-Cdk4 complexes are persistent, albeit reduced by
10022898	Finally, because p16 accumulates in parallel with the increases in senescence-associated beta-Gal activity and cell volume that characterize the senescent phenotype, we suggest that p16 upregulation may be part of a differentiation program that is turned on in senescent cells
10022898	Since p21 decreases after senescence is achieved, this upregulation of p16 may be essential for maintenance of the senescent-cell-cycle arrest
9771890	Expression of a p16INK4a-specific ribozyme downmodulates p16INK4a abundance and accelerates cell proliferation
9771890	To mimic the downmodulation of p16INK4a commonly seen in cancer, we designed and characterized a hammerhead ribozyme against exon E1alpha of the murine pl6INK4a transcript
9771890	The specificity and efficiency of our new ribozyme suggest its possible application in elucidating the role of p16INK4a in fundamental biological processes including homeostatic tissue renewal, protection against oncogenic transformation, and cellular senescence
9732051	In contrast, p16Ink4a, which binds monomeric CDK4 and CDK6 thereby preventing their binding to cyclin D, is increased dramatically at the time of senescence and remains high for at least 2 mo
9732051	Thus, it is possible that increased p21 initiates the senescent cell cycle arrest in normal cells, but p16 is important for the long-term maintenance of that arrest
9704925	In fibroblast systems replicative senescence has been shown to correlate with a number of changes in the expression of the proteins normally regulating progression through the G1 phase of the cell cycle, and recently the Ink4 inhibitor p16 was implicated as a central regulator of replicative senescence in human fibroblasts
9704925	It has, however, been claimed that p16 is not expressed in T-lymphocytes
9704925	There was also an increased binding of p16 to the Cdk6 kinase in senescent cells, and a decreased Cdk6 as well as Cdk2 kinase activity
9607312	The p16INK4A cyclin-dependent kinase (Cdk) inhibitor is now recognized as a major tumor suppressor that is inactivated by a variety of mechanisms in a wide range of human cancers
9607312	It is also implicated in the mechanisms underlying replicative senescence since p16INK4A RNA and protein accumulate as cells approach their proscribed limit of population doublings in tissue culture
9607312	To obtain further evidence of its role in senescence, we have sought ways of overexpressing p16INK4A in primary human diploid fibroblasts (HDF)
9607312	To circumvent the low transfection efficiency of primary cells we have exploited a recombinant form of the full-length p16INK4A protein fused to a 16 amino acid peptide from the Drosophila antennapedia protein
9607312	Here, we show that antennapedia-tagged wild-type p16INK4A protein, but not a functionally compromised tumor-specific variant, causes G1 arrest in early passage HDFs by inhibiting the phosphorylation of the retinoblastoma protein
9607312	These data support a role for p16INK4A in replicative senescence and raise the possibility of using the antennapedia-tagged protein therapeutically
9528853	Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts
9528853	Following the drop in p21 concentration a large increase in the expression level of the tumor suppressor gene p16INK4a is observed
9528853	This scenario, where a transient increase in p21 is followed by a delayed induction of p16INK4a, also happens with the permanent arrest that occurs with cellular senescence
9512419	Senescent cells have a number of characteristics that distinguish them from cycling or quiescent cells including elevated levels of two cyclin-dependent kinase (Cdk) inhibitors, p16INK4a and p21CIP1 [5-11]
9512419	Here, we demonstrate that both of these Cdk inhibitors, as well as other members of their protein families (the INK4 and CIP/KIP families, respectively [12]), induce several facets of the senescent phenotype when ectopically expressed in young human diploid fibroblasts
9512419	A 20 amino acid peptide from p16INK4a that inhibits Cdks active in the G1 phase of the cell cycle [16] produces similar effects in a dose-dependent manner suggesting that, in primary fibroblasts, inhibition of G1-specific Cdk activity is sufficient to induce phenotypic changes that normally occur at the end of their finite lifespan
9508208	Role of the p16 tumor suppressor gene in cancer
9508208	Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer
9508208	The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis
9508208	This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds
9508208	Since then, a high frequency of p16 gene alterations were observed in many primary tumors
9508208	In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation
9508208	Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions
9508208	Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear
9508208	Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers
9436977	Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC)
9436977	Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG
9436977	In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p
9436977	These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro
9436977	Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers
9436977	We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs
9436977	In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0
9436977	Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter
9486850	Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts
9486850	Both immortal lines have lost the wtp53 allele and express no detectable p16INK4a protein, although they carry the p16INK4a gene
9486850	Immunoblots of 5-aza-2'-deoxycytidine-treated cells showed a greatly increased expression of p16INK4a protein but no detectable change in the expression of p21CIP1, a gene known to be strongly expressed in senescent normal human fibroblasts
9486850	In two other experimental series, cells of the two LF lines were infected with retroviral constructs encoding either p16INK4a or p21CIP1
9486850	The results show that induction of senescence in immortal LF fibroblasts can occur by different pathways: (a) by demethylation-dependent pathways that induce the expression of p16INK4a; and (b) by demethylation-independent pathways involving the expression of p21CIP1
9486850	The induction of senescence by p16INK4a and p21CIP1 occurred equally in the two human immortal fibroblast lines, which differed in the length of their telomeres and the activity of their telomerase
9467719	For example, the increased expression of the cyclin-dependent kinase inhibitor p16 may contribute to arresting the growth of senescent cells
9395243	The human protein p19ARF is not detected in hemopoietic human cell lines that abundantly express the alternative beta transcript of the p16INK4a/MTS1 gene
9395243	The p16/MTS1/CDKN2 gene on human chromosome band 9p21 encodes two unrelated proteins: p16INK4a, a specific inhibitor of the cyclin D-dependent kinases CKD4 and CDK6, and the structurally unrelated p19ARF protein that arrests cell growth in G1/S and also in G2/M
9343977	Recent molecular studies indicate that upregulation of two inhibitors of cyclin-dependent kinases, p16 and p21, is responsible for blocking the G1/S transition in senescent cells
9247304	Induction of senescence in human malignant glioma cells by p16INK4A
9247304	We have analysed the significance of the loss of this gene in gliomas by introducing the cDNA for p16INK4A into the human glioma cell line U-1242 MG which has a deleted CDKN2 locus
9247304	We used the tetracycline repressible vector system and obtained two stably transfected clones that expressed p16INK4A upon induction
9247304	This senescence phenotype was dependent on the continuous expression of p16INK4A since it was reversed upon reintroduction of tetracycline suppression
9247304	Thus, the induced expression of p16INK4A in these glioma cells reverted their immortal phenotype and caused an immediate cellular senescence
9244355	Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging
9244355	Four INK4 proteins can prevent cell proliferation by specifically inhibiting cyclin D-dependent kinases
9244355	Both p18INK4c and p19INK4d were widely expressed during mouse embryogenesis, but p16INK4a and p15INK4b were not readily detected prenatally
9244355	Although p15INK4b, p18INK4c and p19INK4d were demonstrated in many tissues by 4 weeks after birth, p16INK4a protein expression was restricted to the lung and spleen of older mice, with increased, more widespread mRNA expression during aging
9244355	Transcripts encoding the INK4a alternative reading frame product p19ARF were not detected before birth but were ubiquitous postnatally
9244355	Expression of p16INK4a and p15INK4b was induced when mouse embryos were disrupted and cultured as mouse embryo 'fibroblasts' (MEFs)
9244355	The levels of p16INK4a and p18INK4c, but not p15INK4b or p19INK4d, further increased as MEFs approached senescence
9244355	Following crisis and establishment, three of four independently-derived cell lines became polyploid and expressed higher levels of functional p16INK4a
9244355	Therefore, loss of p16INK4a and other events predisposing to polyploidy may represent alternative processes contributing to cell immortalization
9244355	Whereas p18INK4c and p19INK4d may regulate pre- and postnatal development, p16INK4a more likely plays a checkpoint function during cell senescence that underscores its selective role as a tumor suppressor
9054499	Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
9054499	However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16
9054499	The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence
9054499	Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells
9303062	Although what genes are involved on chromosome 3 remains speculative, p16 (9p21) and p53 (17p13) are inactivated in a high proportion of oral dysplastic lesions and carcinomas
9303062	Loss of cellular senescence and gain of the immortal phenotype is associated with inactivation of p16 and p53
8943005	Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
8943005	To determine a possible mechanism by which senescent human fibroblasts maintain a hypophosphorylated Rb, we examined the expression levels and interaction of the Rb kinases, CDK4 and CDK6, and the cyclin-dependent kinase inhibitors p21 and p16 in senescent HDFs
8943005	During this period, p16 mRNA and cellular protein levels gradually rose with the protein levels in senescent HDFs reaching nearly 40-fold higher than early passage cells
8943005	In senescent HDFs, p16 was shown to be complexed to both CDK4 and CDK6
8943005	Immunodepletion analysis of p21 and p16 from the senescent cell extracts revealed that p16 is the major CDK inhibitor for both CDK4 and CDK6 kinases
8943005	Based upon these results, we propose that senescence is a multistep process requiring the expression of both p21 and p16
8893868	Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain
8761411	Identification of human tumour suppressor genes by monochromosome transfer: rapid growth-arrest response mapped to 9p21 is mediated solely by the cyclin-D-dependent kinase inhibitor gene, CDKN2A (p16INK4A)
8761411	Subsequent fine-structure deletion mapping of previously uniformative hybrid segregants, employing additional markers between D9S162 and D9S171, provided strong evidence that the cyclin-dependent kinase (cdk) inhibitor gene CDKN2A (p16INK4A) was solely responsible for the chromosome-9 effect; 9p21 microdeletions in a significant proportion of segregant clones were restricted to a single CDKN2A exon
8761411	Transfection experiments with CDKN2A and CDKN2B cDNA expression vectors, using mouse A9 cells and three human malignant melanoma cell lines as recipients, provided further evidence in support of this hypothesis
8761411	Collectively, our results indicate that expression of human CDKN2A (controlled either by its natural regulatory elements, or by a cytomegalovirus promoter) is incompatible with in vitro proliferation in immortalized rodent cells and in human melanoma cell lines
8761411	The rapidity of the growth inhibitory effects of CDKN2A was inconsistent with a mode of action involving induction of replicative cell senescence via telomerase repression, but was consistent with a mechanism based on cell cycle arrest through cdk inhibition
8622687	Human cell lines lacking functional pRB contain high levels of p16 RNA and protein, suggesting a negative feedback loop by which pRB might regulate p16 expression in late G1
8622687	By a combination of nuclear run-on assays and promoter analyses in human fibroblasts expressing a temperature-sensitive simian virus 40 T antigen, we show that p16 transcription is affected by the status of pRB and define a region in the p16 promoter that is required for this response
8622687	However, the effect is not sufficient to account for the differences in p16 RNA levels between pRB-positive and -negative cells
8622687	Moreover, p16 RNA is extremely stable, and the levels do not change appreciably during the cell cycle
8622687	Primary human fibroblasts express very low levels of p16, but the RNA and protein accumulate in late-passage, senescent cells
8622687	The apparent overexpression of p16 in pRB-negative cell lines is therefore caused by at least two factors: loss of repression by pRB and an increase in the number of population doublings
8706801	Fourteen genes, including 3 cyclin-dependent kinase (CDK) inhibitors (p16INK4, p21SDI/CIP/WAF and p27KIP), 5 cyclins, 4 CDKs, Cdi-1, and PCNA were tested in four primary fibroblast strains
8706801	These results corroborate and extend previous observations demonstrating elevated expression of specific cell cycle genes in higher passage cells and suggest that overexpression of the CDK-inhibitors p16INK4 and p21SDI/CIP/WAF, but not p27KIP, may contribute to lower proliferative activity of senescing primary fibroblasts
8706799	These breaks activate a p53 dependent or independent DNA-damage pathway that leads to the induction of a family of inhibitors of cyclin dependent kinases (including p21 and p16) and the eventual G1 block of senescence

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HCSGD entry for CDKN2A

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Gene occurances in abstracts of cellular senescence-associated articles: 704 abstracts the gene occurs.

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