P16

p16 is also known as:

• p16^INK4A
• p16^Ink4
• Cyclin-dependent kinase inhibitor 2A (CDKN2A)
• CDKN2
• CDK 4 Inhibitor
• Multiple Tumor Suppressor 1 (MTS1)
• TP16
• ARF
• MLM
• P14

In humans, p16 is encoded by the CDKN2A gene, located on chromosome 9 (9p21.3). This gene generates several transcript variants that differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4. The remaining transcript includes an alternate exon 1 located 20 kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein that is structurally unrelated to the products of the other variants.{{cite web|last=Hamosh|first=Ada|title=Cyclin-dependent kinase inhibitor 2A; CDKN2A|url=http://www.omim.org/entry/600160|publisher=OMIM|access-date=10 December 2013}} The ARF product functions as a stabilizer of the tumor suppressor protein p53, as it can interact with and sequester MDM2, a protein responsible for the degradation of p53."Molecular biology of cancer", Oxford University Press, 2005, {{ISBN|978-0-19-926472-8}}, Section 5.3{{cite journal | vauthors = Roussel MF | title = The INK4 family of cell cycle inhibitors in cancer | journal = Oncogene | volume = 18 | issue = 38 | pages = 5311–5317 | date = September 1999 | pmid = 10498883 | doi = 10.1038/sj.onc.1202998 | doi-access = free }} In spite of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in controlling the G1 phase of the cell cycle. This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene.

When organisms age, the expression of p16 increases to reduce the proliferation of stem cells.{{cite journal | vauthors = Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE | title = p16INK4a induces an age-dependent decline in islet regenerative potential | journal = Nature | volume = 443 | issue = 7110 | pages = 453–457 | date = September 2006 | pmid = 16957737 | doi = 10.1038/nature05092 | s2cid = 4402013 | bibcode = 2006Natur.443..453K }} This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.

p16 is an inhibitor of cyclin-dependent kinases (CDK). It slows down the cell cycle by prohibiting progression from G1 phase to S phase. Otherwise, CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB). Once phosphorylated, pRB dissociates from the transcription factor E2F1. This liberates E2F1 from its bound state in the cytoplasm and allows it to enter the nucleus. Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.{{cite journal | vauthors = Rayess H, Wang MB, Srivatsan ES | title = Cellular senescence and tumor suppressor gene p16 | journal = International Journal of Cancer | volume = 130 | issue = 8 | pages = 1715–1725 | date = April 2012 | pmid = 22025288 | pmc = 3288293 | doi = 10.1002/ijc.27316 }}{{cite journal | vauthors = Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G | title = Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence | journal = Molecular and Cellular Biology | volume = 16 | issue = 3 | pages = 859–867 | date = March 1996 | pmid = 8622687 | pmc = 231066 | doi = 10.1128/mcb.16.3.859 }}

This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum. On one end, p16 hypermethylation, mutation, or deletion leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression. Conversely, activation of p16 through reactive oxygen species, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells.

Regulation of p16 is complex and involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region.

PRC1 and PRC2 are two protein complexes that modify the expression of p16 through the interaction of various transcription factors that execute methylation patterns that can repress transcription of p16. These pathways are activated in the cellular response to reduce senescence.{{cite journal | vauthors = Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y | title = Role of histone H3 lysine 27 methylation in Polycomb-group silencing | journal = Science | volume = 298 | issue = 5595 | pages = 1039–1043 | date = November 2002 | pmid = 12351676 | doi = 10.1126/science.1076997 | s2cid = 6265267 | bibcode = 2002Sci...298.1039C }}{{cite journal | vauthors = Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K | title = The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells | journal = Genes & Development | volume = 21 | issue = 5 | pages = 525–530 | date = March 2007 | pmid = 17344414 | pmc = 1820894 | doi = 10.1101/gad.415507 }}

Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers, and alterations of the gene are frequently seen in cancer cell lines.{{cite journal | vauthors = Liggett WH, Sidransky D | title = Role of the p16 tumor suppressor gene in cancer | journal = Journal of Clinical Oncology | volume = 16 | issue = 3 | pages = 1197–1206 | date = March 1998 | pmid = 9508208 | doi = 10.1200/JCO.1998.16.3.1197 }}{{cite journal | vauthors = Rocco JW, Sidransky D | title = p16(MTS-1/CDKN2/INK4a) in cancer progression | journal = Experimental Cell Research | volume = 264 | issue = 1 | pages = 42–55 | date = March 2001 | pmid = 11237522 | doi = 10.1006/excr.2000.5149 }} Examples include:

Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene.{{cite journal | vauthors = Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE | title = Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma | journal = Nature Genetics | volume = 8 | issue = 1 | pages = 27–32 | date = September 1994 | pmid = 7726912 | doi = 10.1038/ng0994-27 | s2cid = 23195660 }}{{cite journal | vauthors = Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA, Goodfellow PJ | title = Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas | journal = Genes, Chromosomes & Cancer | volume = 14 | issue = 3 | pages = 189–195 | date = November 1995 | pmid = 8589035 | doi = 10.1002/gcc.2870140306 | s2cid = 22823227 }}{{cite journal | vauthors = Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins R, Hogg D | title = Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma | journal = Oncogene | volume = 11 | issue = 2 | pages = 405–412 | date = July 1995 | pmid = 7624155 }}

Carriers of germline mutations in CDKN2A have, besides their high risks of melanoma, also increased risks of pancreatic, lung, laryngeal and oropharyngeal cancers. Tobacco smoking increases the carriers’ susceptibility for such non-melanoma cancers.{{cite journal | vauthors = Helgadottir H, Höiom V, Jönsson G, Tuominen R, Ingvar C, Borg A, Olsson H, Hansson J | title = High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families | journal = Journal of Medical Genetics | volume = 51 | issue = 8 | pages = 545–552 | date = August 2014 | pmid = 24935963 | pmc = 4112445 | doi = 10.1136/jmedgenet-2014-102320 }}

Homozygous deletions of p16 are frequently found in esophageal cancer and gastric cancer cell lines.{{cite journal | vauthors = Igaki H, Sasaki H, Kishi T, Sakamoto H, Tachimori Y, Kato H, Watanabe H, Sugimura T, Terada M | title = Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines | journal = Biochemical and Biophysical Research Communications | volume = 203 | issue = 2 | pages = 1090–1095 | date = September 1994 | pmid = 8093026 | doi = 10.1006/bbrc.1994.2294 }}

Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer.{{cite journal | vauthors = Puig-Butille JA, Escámez MJ, Garcia-Garcia F, Tell-Marti G, Fabra À, Martínez-Santamaría L, Badenas C, Aguilera P, Pevida M, Dopazo J, del Río M, Puig S | title = Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer | journal = Oncotarget | volume = 5 | issue = 6 | pages = 1439–1451 | date = March 2014 | pmid = 24742402 | pmc = 4039222 | doi = 10.18632/oncotarget.1444 }}

Hypermethylation of tumor suppressor genes has been implicated in various cancers. In 2013, a meta-analysis revealed an increased frequency of DNA methylation of the p16 gene in esophageal cancer. As the degree of tumor differentiation increased, so did the frequency of p16 DNA methylation.

Tissue samples of primary oral squamous cell carcinoma (OSCC) often display hypermethylation in the promoter regions of p16. Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16. This epigenetic change leads to loss of the tumor suppressor gene function through two possible mechanisms: first, methylation can physically inhibit the transcription of the gene, and second, methylation can lead to the recruitment of transcription factors that repress transcription. Both mechanisms cause the same end result: downregulation of gene expression that leads to decreased levels of the p16 protein. It has been suggested that this process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.{{cite journal | vauthors = Khor GH, Froemming GR, Zain RB, Abraham MT, Omar E, Tan SK, Tan AC, Vincent-Chong VK, Thong KL | title = DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma | journal = International Journal of Medical Sciences | volume = 10 | issue = 12 | pages = 1727–1739 | year = 2013 | pmid = 24155659 | pmc = 3805925 | doi = 10.7150/ijms.6884 }}{{cite journal | vauthors = Demokan S, Chuang A, Suoğlu Y, Ulusan M, Yalnız Z, Califano JA, Dalay N | title = Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer | journal = Head & Neck | volume = 34 | issue = 10 | pages = 1470–1475 | date = October 2012 | pmid = 22106032 | doi = 10.1002/hed.21949 | s2cid = 11512476 }}{{cite journal | vauthors = Shaw RJ, Liloglou T, Rogers SN, Brown JS, Vaughan ED, Lowe D, Field JK, Risk JM | title = Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: quantitative evaluation using pyrosequencing | journal = British Journal of Cancer | volume = 94 | issue = 4 | pages = 561–568 | date = February 2006 | pmid = 16449996 | pmc = 2361183 | doi = 10.1038/sj.bjc.6602972 }}{{cite journal | vauthors = Sharma G, Mirza S, Prasad CP, Srivastava A, Gupta SD, Ralhan R | title = Promoter hypermethylation of p16INK4A, p14ARF, CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients | journal = Life Sciences | volume = 80 | issue = 20 | pages = 1873–1881 | date = April 2007 | pmid = 17383681 | doi = 10.1016/j.lfs.2007.02.026 }}{{cite journal | vauthors = Jabłonowski Z, Reszka E, Gromadzińska J, Wąsowicz W, Sosnowski M | title = Hypermethylation of p16 and DAPK promoter gene regions in patients with non-invasive urinary bladder cancer | journal = Archives of Medical Science | volume = 7 | issue = 3 | pages = 512–516 | date = June 2011 | pmid = 22295037 | pmc = 3258754 | doi = 10.5114/aoms.2011.23421 }}{{cite journal | vauthors = Xu R, Wang F, Wu L, Wang J, Lu C | title = A systematic review of hypermethylation of p16 gene in esophageal cancer | journal = Cancer Biomarkers | volume = 13 | issue = 4 | pages = 215–226 | date = January 2013 | pmid = 24240582 | doi = 10.3233/CBM-130355 }}

p16 positivity has been shown to be favorably prognostic in oropharyngeal squamous cell carcinoma.{{cite journal | vauthors = Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML | title = Human papillomavirus and survival of patients with oropharyngeal cancer | journal = The New England Journal of Medicine | volume = 363 | issue = 1 | pages = 24–35 | date = July 2010 | pmid = 20530316 | pmc = 2943767 | doi = 10.1056/NEJMoa0912217 }} In a retrospective trial analysis of patients with Stage III and IV oropharyngeal cancer, HPV status was assessed and it was found that the 3-year rates of overall survival were 82.4% (95% CI, 77.2 to 87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7 to 79.8) and 43.4% (95% CI, 34.4 to 52.4), respectively. p16 status is so prognostic that the AJCC staging system has been revised to include p16 status in oropharyngeal squamous cell cancer group staging.{{cite journal | vauthors = Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP | title = Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual | journal = CA | volume = 67 | issue = 2 | pages = 122–137 | date = March 2017 | pmid = 28128848 | doi = 10.3322/caac.21389 | doi-access = free }} However, some people can have elevated levels of p16 but test negative for HPV and vice versa. This is known as discordant cancer. The 5-year survival for people who test positive for HPV and p16 is 81%, for discordant cancer it is 53–55%, and 40% for those who test negative for p16 and HPV.{{cite journal | vauthors = Mehanna H, Taberna M, von Buchwald C, Tous S, Brooks J, Mena M, Morey F, Grønhøj C, Rasmussen JH, Garset-Zamani M, Bruni L, Batis N, Brakenhoff RH, Leemans CR, Baatenburg de Jong RJ, Klussmann JP, Wuerdemann N, Wagner S, Dalianis T, Marklund L, Mirghani H, Schache A, James JA, Huang SH, O'Sullivan B, Nankivell P, Broglie MA, Hoffmann M, Quabius ES, Alemany L | title = Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis | journal = The Lancet. Oncology | volume = 24 | issue = 3 | pages = 239–251 | date = March 2023 | pmid = 36796393 | doi = 10.1016/s1470-2045(23)00013-x | hdl = 2445/198366 | s2cid = 256860640 | hdl-access = free }}{{Cite journal |title=Testing for both HPV and p16 can give more precise prognoses in oropharyngeal (throat) cancer |url=https://evidence.nihr.ac.uk/alert/testing-for-both-hpv-and-p16-can-give-more-precise-prognoses-in-oropharyngeal-throat-cancer/ |journal=NIHR Evidence|date=2023 |doi=10.3310/nihrevidence_59749 |s2cid=261791439 |url-access=subscription }}

Expression of p16 is used as a prognostic biomarker for certain types of cancer. The reason for this is different types of cancer can have different effects on p16 expression: cancers that overexpress p16 are usually caused by the human papillomavirus (HPV), whereas cancers in which p16 is downregulated will usually have other causes. For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course. Presence of the biomarker is associated with a more favorable prognosis as measured by cancer-specific survival (CSS), recurrence-free survival (RFS), locoregional control (LRC), as well as other measurements. The appearance of hypermethylation of p16 is also being evaluated as a potential prognostic biomarker for prostate cancer.{{cite journal | vauthors = Oguejiofor KK, Hall JS, Mani N, Douglas C, Slevin NJ, Homer J, Hall G, West CM | title = The prognostic significance of the biomarker p16 in oropharyngeal squamous cell carcinoma | journal = Clinical Oncology | volume = 25 | issue = 11 | pages = 630–638 | date = November 2013 | pmid = 23916365 | doi = 10.1016/j.clon.2013.07.003 }}{{cite journal | vauthors = Balgkouranidou I, Liloglou T, Lianidou ES | title = Lung cancer epigenetics: emerging biomarkers | journal = Biomarkers in Medicine | volume = 7 | issue = 1 | pages = 49–58 | date = February 2013 | pmid = 23387484 | doi = 10.2217/bmm.12.111 | doi-access = free }}{{cite journal | vauthors = Sinha P, Thorstad WT, Nussenbaum B, Haughey BH, Adkins DR, Kallogjeri D, Lewis JS | title = Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: a critical analysis of patterns and outcomes | journal = Oral Oncology | volume = 50 | issue = 1 | pages = 45–51 | date = January 2014 | pmid = 24211084 | pmc = 3942323 | doi = 10.1016/j.oraloncology.2013.10.007 }}

p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.{{cite journal | vauthors = Hwang H, Tse C, Rodriguez S, Gown A, Churg A | title = p16 FISH deletion in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma | journal = The American Journal of Surgical Pathology | volume = 38 | issue = 5 | pages = 681–688 | date = May 2014 | pmid = 24503757 | doi = 10.1097/PAS.0000000000000176 | s2cid = 28068784 }}

Image:High grade squamous intraepithelial lesion - 2 - p16 -- high mag.jpg

File:Immunohistochemistry for p16 in uterine papillary serous adenocarcinoma showing both nuclear and cytoplasmic staining.jpg

As consensus grows regarding the strength of p16 as a biomarker for detecting and determining prognoses of cancer, p16 immunohistochemistry is growing in importance.{{cite journal | vauthors = Dreyer JH, Hauck F, Oliveira-Silva M, Barros MH, Niedobitek G | title = Detection of HPV infection in head and neck squamous cell carcinoma: a practical proposal | journal = Virchows Archiv | volume = 462 | issue = 4 | pages = 381–389 | date = April 2013 | pmid = 23503925 | doi = 10.1007/s00428-013-1393-5 | s2cid = 7469046 }}

p16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin. The majority of SCCs of uterine cervix express p16. However, p16 can be expressed in other neoplasms and in several normal human tissues.{{cite journal | vauthors = Cioffi-Lavina M, Chapman-Fredricks J, Gomez-Fernandez C, Ganjei-Azar P, Manoharan M, Jorda M | title = P16 expression in squamous cell carcinomas of cervix and bladder | journal = Applied Immunohistochemistry & Molecular Morphology | volume = 18 | issue = 4 | pages = 344–347 | date = July 2010 | pmid = 20571342 | doi = 10.1097/PAI.0b013e3181d2bbd7 | s2cid = 5065484 }}

More than a third of urinary bladder SCCs express p16. SCCs of urinary bladder express p16 independent of gender. p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.

Concentrations of p16INK4a increase dramatically as tissue ages. p16INK4a, along with senescence-associated beta-galactosidase, is regarded to be a biomarker of cellular senescence.{{cite journal | vauthors = Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A, Chernova OB, Gudkov AV | title = Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells | journal = Aging | volume = 8 | issue = 7 | pages = 1294–1315 | date = July 2016 | pmid = 27391570 | pmc = 4993332 | doi = 10.18632/aging.100991 }} Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.{{cite journal | vauthors = Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE | title = Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging | journal = Aging Cell | volume = 8 | issue = 4 | pages = 439–448 | date = August 2009 | pmid = 19485966 | pmc = 2752333 | doi = 10.1111/j.1474-9726.2009.00489.x }} Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify p16 as belonging to a "core signature" of senescence markers.{{cite journal | vauthors = Hernandez-Segura A, de Jong TV, Melov S, Guryev V, Campisi J, Demaria M | title = Unmasking Transcriptional Heterogeneity in Senescent Cells | journal = Current Biology | volume = 27 | issue = 17 | pages = 2652–2660.e4 | date = September 2017 | pmid = 28844647 | pmc = 5788810 | doi = 10.1016/j.cub.2017.07.033 | bibcode = 2017CBio...27E2652H }}

It has been used as a target to delay some aging changes in mice.{{cite journal | vauthors = Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM | title = Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders | journal = Nature | volume = 479 | issue = 7372 | pages = 232–236 | date = November 2011 | pmid = 22048312 | pmc = 3468323 | doi = 10.1038/nature10600 | bibcode = 2011Natur.479..232B }}

===Role in neurogenesis===

Increasing p16INK4a expression during aging is associated with reduced progenitor functions from the subventricular zone, which generates throughout life new neurons migrating to the olfactory bulb, thereby reducing olfactory neurogenesis.{{cite journal | vauthors = Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ | title = Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing | journal = Nature | volume = 443 | issue = 7110 | pages = 448–452 | date = September 2006 | pmid = 16957738 | pmc = 2586960 | doi = 10.1038/nature05091 | bibcode = 2006Natur.443..448M }} Deletion of p16INK4a does not affect neurogenesis in the other adult neurogenic niche, the dentate gyrus of the hippocampus. However, recently, it has been demonstrated that p16INK4a protects from depletion after a powerful proneurogenic stimulus—i.e., running— also stem and progenitor cells of the aged dentate gyrus.{{cite journal | vauthors = Micheli L, D'Andrea G, Ceccarelli M, Ferri A, Scardigli R, Tirone F | title = p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise | journal = Frontiers in Cellular Neuroscience | volume = 13 | pages = 10 | year = 2019 | pmid = 30792628 | pmc = 6374340 | doi = 10.3389/fncel.2019.00010 | doi-access = free }} In fact, after deletion of p16INK4a, stem cells of the dentate gyrus are greatly activated by running, while, in wild-type p16INK4a dentate gyrus stem cells are not affected by running. Therefore, p16Ink4a plays a role in the maintenance of dentate gyrus stem cells after stimulus, by keeping a reserve of their self-renewal capacity during aging. Since the dentate gyrus plays a key role in spatial and contextual memory formation, p16INK4a is implicated in the maintenance of cognitive functions during aging.

Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor.

==Role in carcinogenesis==

Since its discovery, p16 has become significant in the field of cancer research. The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines. The detection of p16 inactivation in familial melanoma supplied further evidence. p16 deletion, mutation, hypermethylation, or overexpression is now associated with various cancers. Whether mutations in p16 can be considered to be driver mutations requires further investigation.

p16 has been shown to interact with:

{{div col|colwidth=30em}}

• CCNG1,{{cite journal | vauthors = Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE | title = Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways | journal = Molecular Cancer Research | volume = 1 | issue = 3 | pages = 195–206 | date = January 2003 | pmid = 12556559 }}
• CDK4,{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}{{cite journal | vauthors = Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP | title = Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A | journal = Current Biology | volume = 6 | issue = 1 | pages = 84–91 | date = January 1996 | pmid = 8805225 | doi = 10.1016/S0960-9822(02)00425-6 | s2cid = 23024663 | doi-access = free | hdl = 20.500.11820/9e95b5cc-be55-4c50-bfd9-04eb51b3e3f9 | hdl-access = free }}{{cite journal | vauthors = Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR | title = Identification of CDK4 sequences involved in cyclin D1 and p16 binding | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18869–18874 | date = July 1997 | pmid = 9228064 | doi = 10.1074/jbc.272.30.18869 | doi-access = free }}
• CDK6,{{cite journal | vauthors = Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP | title = Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a | journal = Nature | volume = 395 | issue = 6699 | pages = 237–243 | date = September 1998 | pmid = 9751050 | doi = 10.1038/26155 | s2cid = 204997058 | bibcode = 1998Natur.395..237R }}{{cite journal | vauthors = Kaldis P, Ojala PM, Tong L, Mäkelä TP, Solomon MJ | title = CAK-independent activation of CDK6 by a viral cyclin | journal = Molecular Biology of the Cell | volume = 12 | issue = 12 | pages = 3987–3999 | date = December 2001 | pmid = 11739795 | pmc = 60770 | doi = 10.1091/mbc.12.12.3987 }}
• DAXX,{{cite journal | vauthors = Ivanchuk SM, Mondal S, Rutka JT | title = p14ARF interacts with DAXX: effects on HDM2 and p53 | journal = Cell Cycle | volume = 7 | issue = 12 | pages = 1836–1850 | date = June 2008 | pmid = 18583933 | doi = 10.4161/cc.7.12.6025 | doi-access = free }}
• E4F1,
• MDM2,{{cite journal | vauthors = Clark PA, Llanos S, Peters G | title = Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2 | journal = Oncogene | volume = 21 | issue = 29 | pages = 4498–4507 | date = July 2002 | pmid = 12085228 | doi = 10.1038/sj.onc.1205558 | doi-access = free }}{{cite journal | vauthors = Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA | title = The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 | journal = Cell | volume = 92 | issue = 6 | pages = 713–723 | date = March 1998 | pmid = 9529248 | doi = 10.1016/S0092-8674(00)81400-2 | author11-link = Carlos Cordon-Cardo | s2cid = 17190271 | doi-access = free }}
• P53,{{cite journal | vauthors = Rizos H, Diefenbach E, Badhwar P, Woodruff S, Becker TM, Rooney RJ, Kefford RF | title = Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition | journal = The Journal of Biological Chemistry | volume = 278 | issue = 7 | pages = 4981–4989 | date = February 2003 | pmid = 12446718 | doi = 10.1074/jbc.M210978200 | doi-access = free }}{{cite journal | vauthors = Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, Xiong Y | title = Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway | journal = Molecular and Cellular Biology | volume = 23 | issue = 23 | pages = 8902–8912 | date = December 2003 | pmid = 14612427 | pmc = 262682 | doi = 10.1128/MCB.23.23.8902-8912.2003 }}{{cite journal | vauthors = Zhang Y, Xiong Y, Yarbrough WG | title = ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways | journal = Cell | volume = 92 | issue = 6 | pages = 725–734 | date = March 1998 | pmid = 9529249 | doi = 10.1016/S0092-8674(00)81401-4 | s2cid = 334187 | doi-access = free }}
• PPP1R9B,{{cite journal | vauthors = Vivo M, Calogero RA, Sansone F, Calabrò V, Parisi T, Borrelli L, Saviozzi S, La Mantia G | title = The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 17 | pages = 14161–14169 | date = April 2001 | pmid = 11278317 | doi = 10.1074/jbc.M006845200 | doi-access = free }}
• RPL11, and
• SERTAD1.{{cite journal | vauthors = Li J, Melvin WS, Tsai MD, Muscarella P | title = The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner | journal = Biochemistry | volume = 43 | issue = 14 | pages = 4394–4399 | date = April 2004 | pmid = 15065884 | doi = 10.1021/bi035601s | citeseerx = 10.1.1.386.140 }}{{cite journal | vauthors = Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E | title = Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1) | journal = Genes & Development | volume = 13 | issue = 22 | pages = 3027–3033 | date = November 1999 | pmid = 10580009 | pmc = 317153 | doi = 10.1101/gad.13.22.3027 }}

{{Div col end}}

• p21
• p53
• Cyclin-dependent kinase
• Cyclin D

{{Reflist|2}}

• {{MeshName|Genes,+p16}}
• {{UCSC genome browser|CDKN2A}}
• {{UCSC gene details|CDKN2A}}

{{PDB Gallery|geneid=1029}}

{{Cell cycle proteins}}

{{Tumor suppressor genes}}

Category:Tumor suppressor genes

Category:Biomarkers