CDKN2A

The CDKN2A gene resides on chromosome 9 at the band 9p21 and contains 8 exons.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/1029|title=CDKN2A cyclin dependent kinase inhibitor 2A [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2016-10-11}} This gene encodes two proteins, p16 and p14ARF, which are transcribed from the same second and third exons but alternative first exons: p16 from exon 1α and ARF from exon 1β. As a result, they are translated from different reading frames and therefore possess completely different amino acid sequences.{{cite journal | vauthors = Aoude LG, Wadt KA, Pritchard AL, Hayward NK | title = Genetics of familial melanoma: 20 years after CDKN2A | journal = Pigment Cell & Melanoma Research | volume = 28 | issue = 2 | pages = 148–60 | date = March 2015 | pmid = 25431349 | doi = 10.1111/pcmr.12333 | s2cid = 5341669 | doi-access = free }} In addition to p16 and ARF, this gene produces 4 other isoforms through alternative splicing.{{Cite web|url=https://www.uniprot.org/uniprot/P42771|title=CDKN2A - Cyclin-dependent kinase inhibitor 2A - Homo sapiens (Human) - CDKN2A gene & protein|website=www.uniprot.org|access-date=2016-10-11}}

This protein belongs to the CDKN2 cyclin-dependent kinase inhibitor family. p16 comprises four ankyrin repeats, each spanning a length of 33 amino acid residues and, in the tertiary structure, forming a helix-turn-helix motif. One exception is the second ankyrin repeat, which contains only one helical turn. These four motifs are connected by three loops such that they are oriented perpendicular to the helical axes.

According to its solvent-accessible surface representation, p16 features clustered charged groups on its surface and a pocket located on the right side with a negatively charged left inner wall and a positively charged right inner wall.{{cite journal | vauthors = Byeon IJ, Li J, Ericson K, Selby TL, Tevelev A, Kim HJ, O'Maille P, Tsai MD | title = Tumor suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4 | journal = Molecular Cell | volume = 1 | issue = 3 | pages = 421–31 | date = February 1998 | pmid = 9660926 | doi = 10.1016/s1097-2765(00)80042-8 | doi-access = free }}

The size of this protein is 14 kDa in humans.{{cite journal | vauthors = Lo D, Zhang Y, Dai MS, Sun XX, Zeng SX, Lu H | title = Nucleostemin stabilizes ARF by inhibiting the ubiquitin ligase ULF | journal = Oncogene | volume = 34 | issue = 13 | pages = 1688–97 | date = March 2015 | pmid = 24769896 | pmc = 4212020 | doi = 10.1038/onc.2014.103 }} Within the N-terminal half of ARF are highly hydrophobic domains that serve as mitochondrial import sequences.

P14ARF is a central actor of the cell cycle regulation process as it participates to the ARF-MDM2-p53 pathway and the Rb-E2F-1 pathway.{{cite journal | vauthors = Karayan L, Riou JF, Séité P, Migeon J, Cantereau A, Larsen CJ | title = Human ARF protein interacts with topoisomerase I and stimulates its activity | journal = Oncogene | volume = 20 | issue = 7 | pages = 836–48 | date = February 2001 | pmid = 11314011 | doi = 10.1038/sj.onc.1204170 | s2cid = 2801461 | doi-access = }} It is the physiological inhibitor of MDM2, an E3 ubiquitin ligase controlling the activity and stability of P53, and loss of P14ARF activity may have a similar effect as loss of P53.{{cite journal | vauthors = Kanellou P, Zaravinos A, Zioga M, Spandidos DA | title = Deregulation of the tumour suppressor genes p14(ARF), p15(INK4b), p16(INK4a) and p53 in basal cell carcinoma | journal = The British Journal of Dermatology | volume = 160 | issue = 6 | pages = 1215–21 | date = June 2009 | pmid = 19298278 | doi = 10.1111/j.1365-2133.2009.09079.x | s2cid = 29291218 }} P14ARF induces cell cycle arrest in G2 phase and subsequent apoptosis in a P53-dependent and P53-independent manner, and thus is regarded as a tumor suppressor.{{cite journal | vauthors = Huang Y, Tyler T, Saadatmandi N, Lee C, Borgstrom P, Gjerset RA | title = Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability | journal = Cancer Research | volume = 63 | issue = 13 | pages = 3646–53 | date = July 2003 | pmid = 12839954 }}{{cite journal | vauthors = Chen D, Kon N, Li M, Zhang W, Qin J, Gu W | title = ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor | journal = Cell | volume = 121 | issue = 7 | pages = 1071–83 | date = July 2005 | pmid = 15989956 | doi = 10.1016/j.cell.2005.03.037 | s2cid = 16176749 | doi-access = free }}{{cite journal | vauthors = Miao L, Song Z, Jin L, Zhu YM, Wen LP, Wu M | title = ARF antagonizes the ability of Miz-1 to inhibit p53-mediated transactivation | journal = Oncogene | volume = 29 | issue = 5 | pages = 711–22 | date = February 2010 | pmid = 19901969 | doi = 10.1038/onc.2009.372 | doi-access = free }}{{cite journal | vauthors = Eymin B, Leduc C, Coll JL, Brambilla E, Gazzeri S | title = p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice | journal = Oncogene | volume = 22 | issue = 12 | pages = 1822–35 | date = March 2003 | pmid = 12660818 | doi = 10.1038/sj.onc.1206303 | doi-access = free | url = https://www.hal.inserm.fr/inserm-02345413/file/Eymin%20et%20al%20Oncogene%202003.pdf }} In addition, P14ARF could down-regulate E2F-dependent transcription and plays a role in the control of the G1 to S phase transition as well.{{cite journal | vauthors = Mason SL, Loughran O, La Thangue NB | title = p14(ARF) regulates E2F activity | journal = Oncogene | volume = 21 | issue = 27 | pages = 4220–30 | date = June 2002 | pmid = 12082609 | doi = 10.1038/sj.onc.1205524 | s2cid = 8866243 | doi-access = }}

P16 interacts with Rb and controls the G1 to S transition. It binds to CDK4/6 inhibiting its kinase activity and prevents Rb phosphorylation. Therefore, Rb remains associated with transcription factor E2F1, preventing transcription of E2F1 target genes which are crucial for the G1/S transition. During this process, a feedback loop exists between P16 and Rb, and P16 expression is controlled by Rb.{{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 = 1715–25 | date = April 2012 | pmid = 22025288 | pmc = 3288293 | doi = 10.1002/ijc.27316 }}{{cite journal | vauthors = Li Y, Nichols MA, Shay JW, Xiong Y | title = Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb | journal = Cancer Research | volume = 54 | issue = 23 | pages = 6078–82 | date = December 1994 | pmid = 7954450 }} P16/Rb pathway collaborates with the mitogenic signaling cascade for the induction of reactive oxygen species, which activates the protein kinase C delta, leading to an irreversible cell cycle arrest. Thus P16 participates not only in the initiation but also in the maintenance of cellular senescence, as well in tumor suppression.{{cite journal | vauthors = Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E | title = Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence | journal = Nature Cell Biology | volume = 8 | issue = 11 | pages = 1291–7 | date = November 2006 | pmid = 17028578 | doi = 10.1038/ncb1491 | s2cid = 8686894 }}{{cite journal | vauthors = Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES | title = The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments | journal = Cell Cycle | volume = 10 | issue = 15 | pages = 2497–503 | date = August 2011 | pmid = 21775818 | pmc = 3685613 | doi = 10.4161/cc.10.15.16776 }} On the other hand, some specific tumors harbor high levels of P16, and its function in limitation of tumorigenic progression has been inactivated via the loss of Rb.{{cite journal | vauthors = Kelley MJ, Nakagawa K, Steinberg SM, Mulshine JL, Kamb A, Johnson BE | title = Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines | journal = Journal of the National Cancer Institute | volume = 87 | issue = 10 | pages = 756–61 | date = May 1995 | pmid = 7563154 | doi = 10.1093/jnci/87.10.756 | url = https://zenodo.org/record/1234357 }}

In human cancer cell lines derived from various tumor types, a high frequency of genetic and epigenetic alterations (e.g., promoter hyper-methylation, homozygous deletion or mutation) in the CDKN2A gene has been observed. Accordingly, epigenetic/genetic modulation of changes in CDKN2A might be a promising strategy for prevention or therapy of cancer.

The CDKN2A gene is located on the chromosome 9p21 locus, which is intriguing for several reasons. First, this region is well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma.{{cite journal | vauthors = Hayward NK | title = Genetics of melanoma predisposition | journal = Oncogene | volume = 22 | issue = 20 | pages = 3053–62 | date = May 2003 | pmid = 12789280 | doi = 10.1038/sj.onc.1206445 | s2cid = 20268281 | doi-access = }} Second, genome wide association studies have reported a significant association of chromosome 9p21 with coronary artery disease and myocardial infarction{{cite journal | vauthors = McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC | title = A common allele on chromosome 9 associated with coronary heart disease | journal = Science | volume = 316 | issue = 5830 | pages = 1488–91 | date = June 2007 | pmid = 17478681 | pmc = 2711874 | doi = 10.1126/science.1142447 | bibcode = 2007Sci...316.1488M }} as well as the progression of atherosclerosis.{{cite journal | vauthors = Ye S, Willeit J, Kronenberg F, Xu Q, Kiechl S | title = Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study | journal = Journal of the American College of Cardiology | volume = 52 | issue = 5 | pages = 378–84 | date = July 2008 | pmid = 18652946 | doi = 10.1016/j.jacc.2007.11.087 | doi-access = }}

Furthermore, changes in CDKN2A status are highly variable depending on the type of cancer. In addition to skin cancer such as melanoma, changes of CDKN2A have been described in a wide spectrum of cancer types such as gastric lymphoma,{{cite journal | vauthors = Huang Q, Su X, Ai L, Li M, Fan CY, Weiss LM | title = Promoter hypermethylation of multiple genes in gastric lymphoma | journal = Leukemia & Lymphoma | volume = 48 | issue = 10 | pages = 1988–96 | date = October 2007 | pmid = 17852707 | doi = 10.1080/10428190701573224 | s2cid = 72186314 }} Burkitt's lymphoma,{{cite journal | vauthors = Robaina MC, Faccion RS, Arruda VO, de Rezende LM, Vasconcelos GM, Apa AG, Bacchi CE, Klumb CE | title = Quantitative analysis of CDKN2A methylation, mRNA, and p16(INK4a) protein expression in children and adolescents with Burkitt lymphoma: biological and clinical implications | journal = Leukemia Research | volume = 39 | issue = 2 | pages = 248–56 | date = February 2015 | pmid = 25542698 | doi = 10.1016/j.leukres.2014.11.023 }} head & neck squamous cell carcinoma,{{cite journal | vauthors = El-Naggar AK, Lai S, Clayman G, Lee JK, Luna MA, Goepfert H, Batsakis JG | title = Methylation, a major mechanism of p16/CDKN2 gene inactivation in head and neck squamous carcinoma | journal = The American Journal of Pathology | volume = 151 | issue = 6 | pages = 1767–74 | date = December 1997 | pmid = 9403727 | pmc = 1858347 }} glioma,{{cite journal |last1=Mandigo |first1=Amy C |last2=Tomlins |first2=Scott A |last3=Kelly |first3=William K |last4=Knudsen |first4=Karen E |title=Relevance of pRB Loss in Human Malignancies |journal=Clinical Cancer Research |date=January 19, 2022 |volume=28 |issue=2 |page=Table 1 |doi=10.1158/1078-0432.CCR-21-1565 |pmid=34407969 |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC9306333/ |access-date=17 January 2025|pmc=9306333 }} oral cancer,{{cite journal | vauthors = Asokan GS, Jeelani S, Gnanasundaram N | title = Promoter hypermethylation profile of tumour suppressor genes in oral leukoplakia and oral squamous cell carcinoma | journal = Journal of Clinical and Diagnostic Research | volume = 8 | issue = 10 | pages = ZC09-12 | date = October 2014 | pmid = 25478438 | pmc = 4253256 | doi = 10.7860/JCDR/2014/9251.4949 }} pancreatic adenocarcinoma,{{cite journal | vauthors = Jiao L, Zhu J, Hassan MM, Evans DB, Abbruzzese JL, Li D | title = K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking | journal = Pancreas | volume = 34 | issue = 1 | pages = 55–62 | date = January 2007 | pmid = 17198183 | pmc = 1905887 | doi = 10.1097/01.mpa.0000246665.68869.d4 }} non-small cell lung carcinomas, {{cite journal | vauthors = Marchetti A, Buttitta F, Pellegrini S, Bertacca G, Chella A, Carnicelli V, Tognoni V, Filardo A, Angeletti CA, Bevilacqua G | title = Alterations of P16 (MTS1) in node-positive non-small cell lung carcinomas | journal = The Journal of Pathology | volume = 181 | issue = 2 | pages = 178–82 | date = February 1997 | pmid = 9120722 | doi = 10.1002/(SICI)1096-9896(199702)181:2<178::AID-PATH741>3.0.CO;2-5 | s2cid = 20155703 }} esophageal squamous cell carcinoma,{{cite journal | vauthors = Qureshi MA, Jan N, Dar NA, Hussain M, Andrabi KI | title = A novel p16(INK4A) mutation associated with esophageal squamous cell carcinoma in a high risk population | journal = Biomarkers | volume = 17 | issue = 6 | pages = 552–6 | date = September 2012 | pmid = 22724384 | doi = 10.3109/1354750X.2012.699556 | s2cid = 19678492 }} gastric cancer,{{cite journal | vauthors = He D, Zhang YW, Zhang NN, Zhou L, Chen JN, Jiang Y, Shao CK | title = Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas | journal = Medical Oncology | volume = 32 | issue = 4 | pages = 92 | date = April 2015 | pmid = 25720522 | doi = 10.1007/s12032-015-0525-y | s2cid = 38800637 }} bladder cancer, osteosarcoma, colorectal cancer,{{cite journal | vauthors = Rajendran P, Dashwood WM, Li L, Kang Y, Kim E, Johnson G, Fischer KA, Löhr CV, Williams DE, Ho E, Yamamoto M, Lieberman DA, Dashwood RH | title = Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon | journal = Clinical Epigenetics | volume = 7 | pages = 102 | date = 2015-01-01 | issue = 1 | pmid = 26388957 | pmc = 4575421 | doi = 10.1186/s13148-015-0132-y | doi-access = free }} breast cancer, cervical cancer, epithelial ovarian carcinoma,{{cite journal | vauthors = Bhagat R, Kumar SS, Vaderhobli S, Premalata CS, Pallavi VR, Ramesh G, Krishnamoorthy L | title = Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma | journal = Tumour Biology | volume = 35 | issue = 9 | pages = 9069–78 | date = September 2014 | pmid = 24913706 | doi = 10.1007/s13277-014-2136-1 | s2cid = 1766337 }} endometrial cancer and prostate cancer.{{cite journal | vauthors = Ameri A, Alidoosti A, Hosseini SY, Parvin M, Emranpour MH, Taslimi F, Salehi E, Fadavip P | title = Prognostic Value of Promoter Hypermethylation of Retinoic Acid Receptor Beta (RARB) and CDKN2 (p16/MTS1) in Prostate Cancer | journal = Chinese Journal of Cancer Research = Chung-Kuo Yen Cheng Yen Chiu | volume = 23 | issue = 4 | pages = 306–11 | date = December 2011 | pmid = 23358881 | pmc = 3551302 | doi = 10.1007/s11670-011-0306-x }}

CDKN2A is made up of four sections of exons – exon 1β, exon 1α, exon 2, and exon 3. These exons are used to create two proteins named p16 and p14ARF. Protein p16, created by exon 1α and exon 2, is responsible for tumor creation of genetic melanoma. When working normally, p16 binds to the cyclin dependent kinases CDK4 to inhibit their ability to create tumors, but when inactivated the suppression no longer occurs.{{cite journal | vauthors = Tsao H, Niendorf K | title = Genetic testing in hereditary melanoma | journal = Journal of the American Academy of Dermatology | volume = 51 | issue = 5 | pages = 803–8 | date = November 2004 | pmid = 15523363 | doi = 10.1016/j.jaad.2004.04.045 }} When a mutation occurs in protein p16, it prevents the protein kinase of CDK4, which results in the inactivation of the tumor suppressor gene. This starts the development of melanoma.

Melanoma only occurs in a small proportion of the population. If only two family members have melanoma, there is a 5% chance somebody in the next generation will acquire the mutated gene. Also, there is a 20-40% chance of getting hereditary melanoma in a family if 3 or more people in the past generation had melanoma. For those who carry the hereditary mutated gene CDKN2A, acquiring skin cancer is a lot easier.{{cite journal | vauthors = Kefford R, Bishop JN, Tucker M, Bressac-de Paillerets B, Bianchi-Scarrá G, Bergman W, Goldstein A, Puig S, Mackie R, Elder D, Hansson J, Hayward N, Hogg D, Olsson H | title = Genetic testing for melanoma | journal = The Lancet. Oncology | volume = 3 | issue = 11 | pages = 653–4 | date = November 2002 | pmid = 12424065 | doi = 10.1016/s1470-2045(02)00894-x }} Those who have the gene are far more likely to get melanoma a second or third time compared to those who don't genetically have this gene.{{cite journal | vauthors = Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA | title = Geographical variation in the penetrance of CDKN2A mutations for melanoma | journal = Journal of the National Cancer Institute | volume = 94 | issue = 12 | pages = 894–903 | date = June 2002 | pmid = 12072543 | doi = 10.1093/jnci/94.12.894 | doi-access = free }} The population that is affected by this mutation has a high familial history of melanoma or atypical moles and birth marks in large numbers, a history of primary melanoma/cancers in general, immunosuppression, skin that burns easily and doesn't tan, freckling, blue eyes, red hair, or a history of blistering. People with these high risk factors are more likely to carry inherited mutations in CDKN2A. For those who have a gene mutation, the severity is also dependent on the environmental surroundings. Out of those who carry the gene, those who express the phenotype and actually developed melanoma have a history of more sun exposure, and light skin compared to those who also had the gene but never actually developed melanoma. This suggests that this gene co-works with ones surrounding environment. If two individuals are selected who carry the CDKN2A mutation, and both genetically have the same probability of acquiring skin cancer, but one is from Australia and the other is from Europe, there is a 58% the European will acquire cancer compared to a 91% chance the Australian will get it. This is because the factors mentioned earlier pertaining to those who are more susceptible to the disease and also dependent on the amount of sunscreen one wears and the UV radiation potency in their environment.

A multi-locus genetic risk score study based on a combination of 27 loci, including the CDKN2A gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, Nordio F, Hyde C, Cannon CP, Sacks F, Poulter N, Sever P, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–2271 | date = June 2015 | pmid = 25748612 | pmc = 4608367 | doi = 10.1016/S0140-6736(14)61730-X }}

Activation of the CDKN2A locus promotes the cellular senescence tumor suppressor mechanism, which is a permanent form of growth arrest. As senescent cells accumulate with aging, expression of CDKN2A increases exponentially with aging in all mammalian species tested to date, and has been argued to serve as a biomarker of physiological age.{{cite journal | vauthors = Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE | title = Ink4a/Arf expression is a biomarker of aging | journal = The Journal of Clinical Investigation | volume = 114 | issue = 9 | pages = 1299–307 | date = November 2004 | pmid = 15520862 | pmc = 524230 | doi = 10.1172/JCI22475 }} Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify CDKN2A 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 }}

A variant in the CDKN2A locus present in the founder of Bernese mountain dogs around 200 years ago predisposes the breed to histiocytic sarcoma.{{cite journal | vauthors = Shearin AL, Hedan B, Cadieu E, Erich SA, Schmidt EV, Faden DL, Cullen J, Abadie J, Kwon EM, Gröne A, Devauchelle P, Rimbault M, Karyadi DM, Lynch M, Galibert F, Breen M, Rutteman GR, André C, Parker HG, Ostrander EA | title = The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 21 | issue = 7 | pages = 1019–27 | date = July 2012 | pmid = 22623710 | pmc = 3392365 | doi = 10.1158/1055-9965.EPI-12-0190-T }}

{{Reflist|32em}}

• {{cite journal | vauthors = Irvine M, Philipsz S, Frausto M, Mijatov B, Gallagher SJ, Fung C, Becker TM, Kefford RF, Rizos H | title = Amino terminal hydrophobic import signals target the p14(ARF) tumor suppressor to the mitochondria | journal = Cell Cycle | volume = 9 | issue = 4 | pages = 829–39 | date = February 2010 | pmid = 20107316 | doi = 10.4161/cc.9.4.10785 | doi-access = free }}

• {{UCSC gene info|CDKN2A}}

Category:Genes