Genomes and Genes
cyclin dependent kinase inhibitor p16
Summary: A product of the p16 tumor suppressor gene (GENES, P16). It is also called INK4 or INK4A because it is the prototype member of the INK4 CYCLIN-DEPENDENT KINASE INHIBITORS. This protein is produced from the alpha mRNA transcript of the p16 gene. The other gene product, produced from the alternatively spliced beta transcript, is TUMOR SUPPRESSOR PROTEIN P14ARF. Both p16 gene products have tumor suppressor functions.
- Maeda T, Hobbs R, Merghoub T, Guernah I, Zelent A, Cordon Cardo C, et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature. 2005;433:278-85 pubmed..Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention. ..
- de Jonge H, de Bont E, Valk P, Schuringa J, Kies M, Woolthuis C, et al. AML at older age: age-related gene expression profiles reveal a paradoxical down-regulation of p16INK4A mRNA with prognostic significance. Blood. 2009;114:2869-77 pubmed publisher..We conclude that, in addition to altered clinical and biologic characteristics, AML presenting at older age shows different gene expression profiles. ..
- Haferkamp S, Scurr L, Becker T, Frausto M, Kefford R, Rizos H. Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors. J Invest Dermatol. 2009;129:1983-91 pubmed publisher..Our data are consistent with observations showing that senescent nevus cells do not always express p16(INK4a), and highlight the need to thoroughly explore INK4a/ARF-independent molecular pathways of senescence in human melanocytes. ..
- Liu Y, Sanoff H, Cho H, Burd C, Torrice C, Ibrahim J, et al. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8:439-48 pubmed publisher..These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age. ..
- Lassen P, Eriksen J, Hamilton Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27:1992-8 pubmed publisher..36; 95% CI, 0.20 to 0.64), and overall death (HR, 0.44; 95% CI, 0.28 to 0.68). Expression of p16(INK4A) has a major impact on treatment response and survival in patients with head and neck cancer treated with conventional radiotherapy. ..
- Barradas M, Anderton E, Acosta J, Li S, Banito A, Rodriguez Niedenführ M, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23:1177-82 pubmed publisher..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. ..
- Utikal J, Polo J, Stadtfeld M, Maherali N, Kulalert W, Walsh R, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009;460:1145-8 pubmed publisher..Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis. ..
- Zhang X, Sheng Y, Li Q, Qin W, Lu Y, Cheng Y, et al. BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer. Mol Cancer. 2010;9:40 pubmed publisher..Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT-dependent growth regulatory pathways. ..
- Hu C, Zhang R, Wang C, Wang J, Ma X, Lu J, et al. PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population. PLoS ONE. 2009;4:e7643 pubmed publisher..0006). The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively. ..
- Molofsky A, Pardal R, Iwashita T, Park I, Clarke M, Morrison S. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003;425:962-7 pubmed..Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues. ..
- Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009;460:1136-9 pubmed publisher..All together, we conclude that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells. ..
- Maertens G, El Messaoudi Aubert S, Racek T, Stock J, Nicholls J, Rodriguez Niedenführ M, et al. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus. PLoS ONE. 2009;4:e6380 pubmed publisher..Our findings provide the first evidence that a single gene can be regulated by several distinct PRC1 complexes and raise important questions about their configuration and relative functions. ..
- Agherbi H, Gaussmann Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M. Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PLoS ONE. 2009;4:e5622 pubmed publisher..Together, these results provide a unified model that integrates replication, transcription and epigenetics at the INK4/ARF locus. ..
- Agger K, Cloos P, Rudkjaer L, Williams K, Andersen G, Christensen J, et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23:1171-6 pubmed publisher..Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization. ..
- Zhang Y, Herbert B, Rajashekhar G, Ingram D, Yoder M, Clauss M, et al. Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-alpha via the p38 mitogen-activated protein kinase pathway. FASEB J. 2009;23:1358-65 pubmed publisher..These findings will lead to a better understanding of physiological endothelial regeneration as well as to targeted therapies with the aim of promoting endothelial regeneration through endothelial progenitor cells. ..
- Matheu A, Maraver A, Collado M, Garcia Cao I, Canamero M, Borras C, et al. Anti-aging activity of the Ink4/Arf locus. Aging Cell. 2009;8:152-61 pubmed publisher..We conclude that the Ink4/Arf locus has a global anti-aging effect, probably by favouring quiescence and preventing unnecessary proliferation. ..
- Fargnoli M, Gandini S, Peris K, Maisonneuve P, Raimondi S. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur J Cancer. 2010;46:1413-20 pubmed publisher..A significant anticipation of melanoma diagnosis is observed in CDKN2A mutation carriers with MC1R variants. ..
- Baker D, Perez Terzic C, Jin F, Pitel K, Pitel K, Niederlander N, et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008;10:825-36 pubmed publisher..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. ..
- Chen Z, Carracedo A, Lin H, Koutcher J, Behrendt N, Egia A, et al. Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. Sci Signal. 2009;2:ra44 pubmed publisher..Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway. ..
- Yao C, Kok L, Lee M, Wang P, Wu T, Tyan Y, et al. Ancillary p16(INK4a) adds no meaningful value to the performance of ER/PR/Vim/CEA panel in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet. 2009;280:405-13 pubmed publisher..Ancillary p16(INK4a)-marker testing does not add value to the 4-marker panel in distinguishing between primary ECA and EMA. ..
- Lüdtke T, Christoffels V, Petry M, Kispert A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology. 2009;49:969-78 pubmed publisher..Tbx3 controls liver bud expansion by suppressing cholangiocyte and favoring hepatocyte differentiation in the liver bud. ..
- Kreuter A, Gambichler T, Pfister H, Wieland U. Diversity of human papillomavirus types in periungual squamous cell carcinoma. Br J Dermatol. 2009;161:1262-9 pubmed publisher..Given the high recurrence rate and high proliferative activity of HPV-associated periungual SCCs, aggressive treatment and close follow-up of these tumours is mandatory. ..
- Chapman E, Williams S, Platt F, Hurst C, Chambers P, Roberts P, et al. Integrated genomic and transcriptional analysis of the in vitro evolution of telomerase-immortalized urothelial cells (TERT-NHUC). Genes Chromosomes Cancer. 2009;48:694-710 pubmed publisher..Loss of a region on 2q including BOK was identified in UC cell lines and primary tumors. DNER and FRAS1 were identified as potential candidate genes, whose expression is altered independently of the acquisition of any genetic event. ..
- Duffy D, Iles M, Glass D, Zhu G, Barrett J, Höiom V, et al. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am J Hum Genet. 2010;87:6-16 pubmed publisher..14, p = 0.0035; excluding Australian, the UK, and Swedish samples typed at rs12203592: OR 1.08, p = 0.08). ..
- Lewis J, Thorstad W, Chernock R, Haughey B, Yip J, Zhang Q, et al. p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol. 2010;34:1088-96 pubmed publisher..Many recommend use of both p16 immunohistochemistry and HPV in situ hybridization (ISH). A significant minority of tumors are p16 positive and HPV ISH negative, the significance of which is unclear...
- Jonsson A, Tuominen R, Grafström E, Hansson J, Egyhazi S. High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma. J Invest Dermatol. 2010;130:2809-17 pubmed publisher..Interestingly, p16(INK4A) promoter methylation was significantly overrepresented in NRAS-mutated samples compared to NRAS wild-type samples (P=0.0004), indicating an association between these two events. ..
- Tsygankov D, Liu Y, Sanoff H, Sharpless N, Elston T. A quantitative model for age-dependent expression of the p16INK4a tumor suppressor. Proc Natl Acad Sci U S A. 2009;106:16562-7 pubmed publisher..This analysis is most consistent with the model that p16(INK4a) expression monotonically increases with age, and higher expression is associated with increased subject attrition. ..
- Boquoi A, Chen T, Enders G. Chemoprevention of mouse intestinal tumorigenesis by the cyclin-dependent kinase inhibitor SNS-032. Cancer Prev Res (Phila). 2009;2:800-6 pubmed publisher..005). These results show the chemoprevention of intestinal tumorigenesis by SNS-032. Our findings support further study of Cdk inhibitors for chemoprevention and therapy of colon cancer. ..
- Bigot A, Klein A, Gasnier E, Jacquemin V, Ravassard P, Butler Browne G, et al. Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells. Am J Pathol. 2009;174:1435-42 pubmed publisher..This mechanism is responsible for the reduced proliferative capacity of the DM1 muscle precursor cells and could participate in both the impaired regeneration and atrophy observed in the DM1 muscles containing large CTG expansions. ..
- Crea F, Giovannetti E, Cortesi F, Mey V, Nannizzi S, Gallegos Ruiz M, et al. Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines. Mol Cancer Ther. 2009;8:1964-73 pubmed publisher..In conclusion, 5-aza modulates Top-I expression by several mechanisms involving Sp1, p16, and p53. If confirmed in other models, these results suggest that p16 and p53 status affects the 5-aza-irinotecan interaction. ..
- Shah A, Evans M, Adamson C, Peng Z, Rajendran V, Cooper K. HPV DNA is associated with a subset of Schneiderian papillomas but does not correlate with p16(INK4a) immunoreactivity. Head Neck Pathol. 2010;4:106-12 pubmed publisher..00). In summary, this study demonstrates a strong association between HPV and EPs, however, its role in IPs remains less well-defined. Further, p16(INK4a) is not a useful surrogate marker for HPV detection across the various SPs. ..
- Zhou R, Han L, Li G, Tong T. Senescence delay and repression of p16INK4a by Lsh via recruitment of histone deacetylases in human diploid fibroblasts. Nucleic Acids Res. 2009;37:5183-96 pubmed publisher..Our data suggest that Lsh represses endogenous p16(INK4a) expression by recruiting HDAC to establish a repressive chromatin structure at the p16(INK4a) promoter, which in turn delays cell senescence. ..
- Schmidt M, Asirvatham A, Chaudhary J. Inhibitor of differentiation 1 (ID1) promotes cell survival and proliferation of prostate epithelial cells. Cell Mol Biol Lett. 2010;15:272-95 pubmed publisher..The associated molecular/gene expression profile of Id1-RPE cells provides an opportunity to understand the molecular pathways associated with prostate epithelial cell survival and proliferation. ..
- Zhang W, Zeng Z, Zhou Y, Xiong W, Fan S, Xiao L, et al. Identification of aberrant cell cycle regulation in Epstein-Barr virus-associated nasopharyngeal carcinoma by cDNA microarray and gene set enrichment analysis. Acta Biochim Biophys Sin (Shanghai). 2009;41:414-28 pubmed..These results suggested that cell cycle pathway was the most disregulated pathway in the EBV-associated NPC, and EBER-1 was closely associated with p16, CDK4, cyclin D1, and Rb.cyclin D1 could be the prognosis biomarker for NPC. ..
- Yu L, Wang L, Zhong J, Chen S. Diagnostic value of p16INK4A, Ki-67, and human papillomavirus L1 capsid protein immunochemical staining on cell blocks from residual liquid-based gynecologic cytology specimens. Cancer Cytopathol. 2010;118:47-55 pubmed publisher..A combined expression pattern of p16 and HPV L1 may serve as a valuable index for predicting prognosis and follow-up of cervical dysplastic lesions...
- Yao J, Zhang L, Zhang X, He Z, Ma Y, Hui L, et al. H3K27 trimethylation is an early epigenetic event of p16INK4a silencing for regaining tumorigenesis in fusion reprogrammed hepatoma cells. J Biol Chem. 2010;285:18828-37 pubmed publisher..This unique chromatin pattern may be a heritable marker of epigenetic regulation for p16(INK4a) silencing during the developmental process of hepatocellular carcinogenesis. ..
- Klein M, Mayo K, Kratzke R. p16(INK4a) Peptide mimetics identified via virtual screening. Bioorg Med Chem Lett. 2010;20:403-5 pubmed publisher..Four compounds were subsequently shown to inhibit Cdk4 and/or Cdk6 with IC(50) in the muM range. These compounds form lead compounds upon which further cell cycle inhibitors can be developed. ..
- He S, Iwashita T, Buchstaller J, Molofsky A, Thomas D, Morrison S. Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivo. Dev Biol. 2009;328:257-72 pubmed publisher..Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo. ..
- Nakazawa K, Murata S, Yuminamochi T, Ishii Y, Ohno S, Nakazawa T, et al. p16(INK4a) expression analysis as an ancillary tool for cytologic diagnosis of urothelial carcinoma. Am J Clin Pathol. 2009;132:776-84 pubmed publisher..Immunocytologic analysis of p16(INK4a) expression in cytologic samples is a useful ancillary tool for detection of urothelial carcinoma with infiltrating potential. ..
- Chaudhry P, Srinivasan R, Patel F. Utility of gene promoter methylation in prediction of response to platinum-based chemotherapy in epithelial ovarian cancer (EOC). Cancer Invest. 2009;27:877-84 pubmed publisher..037) and a higher MI (p = .045) were associated with primary chemosensitivity. A better outcome was predicted by a higher MI (p = .032). In EOC, BRCA1 gene promoter methylation is useful in the prediction of response to chemotherapy. ..
- Napier C, Veas L, Kan C, Taylor L, Yuan J, Wen V, et al. Mild hyperoxia limits hTR levels, telomerase activity, and telomere length maintenance in hTERT-transduced bone marrow endothelial cells. Biochim Biophys Acta. 2010;1803:1142-53 pubmed publisher..Overall, these results demonstrate that hTR levels are reduced by mild hyperoxia and limit telomerase-mediated telomere lengthening in hTERT-transduced ECs. ..
- Pirog E, Quint K, Yantiss R. P16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction. Am J Surg Pathol. 2010;34:1449-55 pubmed publisher..These results indicate that a combination of these markers may aid interpretation of anal mucosal biopsy samples. ..
- Wong E, Le Guezennec X, Demidov O, Marshall N, Wang S, Krishnamurthy J, et al. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell. 2009;17:142-9 pubmed publisher..We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases. ..
- Dhawan S, Tschen S, Bhushan A. Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. Genes Dev. 2009;23:906-11 pubmed publisher..We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control beta-cell proliferation during aging and regeneration. ..
- Li H, Wang W, Liu X, Paulson K, Yee A, Zhang X. Transcriptional factor HBP1 targets P16(INK4A), upregulating its expression and consequently is involved in Ras-induced premature senescence. Oncogene. 2010;29:5083-94 pubmed publisher..All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis. ..
- Denton K, Bergeron C, Klement P, Trunk M, Keller T, Ridder R. The sensitivity and specificity of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin Pathol. 2010;134:12-21 pubmed publisher..3% to 53.3% (p16 cytology) vs 18.5% for HPV in LSIL (P < .001). This evaluation of the diagnostic performance of p16 cytology confirms the potential of this stain for the efficient triage of ASC-US and LSIL cytologic results. ..
- Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol. 2010;28:3182-90 pubmed publisher..We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria...
- Ta V, de Bruijn M, ter Brugge P, van Hamburg J, Diepstraten H, Van Loo P, et al. Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway. Blood. 2010;115:1385-93 pubmed publisher..These data indicate that malignant transformation of Slp65(-/-) pre-B cells involves disruption of the p19(Arf)-Mdm2-p53 tumor suppressor pathway. ..
- Wiesner T, Obenauf A, Cota C, Fried I, Speicher M, Cerroni L. Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol. 2010;130:1152-7 pubmed publisher..The elucidation of the affected pathways may guide the development of new treatments specifically designed for this aggressive disease entity. ..
- Simpson D, Mason Richie N, Gettler C, Wikenheiser Brokamp K. Retinoblastoma family proteins have distinct functions in pulmonary epithelial cells in vivo critical for suppressing cell growth and tumorigenesis. Cancer Res. 2009;69:8733-41 pubmed publisher..Taken together, these studies identify distinct Rb family functions critical in controlling epithelial cell growth, and provide direct evidence that p107 cooperates with Rb to protect against a common adult cancer. ..
- Altavilla G, Staffieri A, Busatto G, Canesso A, Giacomelli L, Marioni G. Expression of p53, p16INK4A, pRb, p21WAF1/CIP1, p27KIP1, cyclin D1, Ki-67 and HPV DNA in sinonasal endophytic Schneiderian (inverted) papilloma. Acta Otolaryngol. 2009;129:1242-9 pubmed publisher..15%); HPV + p53+, 2 (10.52%); HPV - p53+, 3 (15.78%) and HPV - p53-, 2 (10.52%). Statistical analysis showed that HPV presence correlated with p53-positive immunostaining (p=0.045). ..
- Sashida G, Liu Y, Elf S, Miyata Y, Ohyashiki K, Izumi M, et al. ELF4/MEF activates MDM2 expression and blocks oncogene-induced p16 activation to promote transformation. Mol Cell Biol. 2009;29:3687-99 pubmed publisher..Thus, ELF4/MEF promotes tumorigenesis by inhibiting both the p53 and p16/Rb pathways. ..
- WILSON B, Wang X, Shen X, McKenna E, Lemieux M, Cho Y, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010;18:316-28 pubmed publisher..Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. ..
- He J, Kallin E, Tsukada Y, Zhang Y. The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). Nat Struct Mol Biol. 2008;15:1169-75 pubmed publisher..Alteration of Jhdm1b level affects Ras-induced neoplastic transformation. Collectively, our results indicate that Jhdm1b is an H3K36 demethylase that regulates cell proliferation and senescence through p15(Ink4b). ..