The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

CDKN2A  -  cyclin-dependent kinase inhibitor 2A

Homo sapiens

Synonyms: ARF, CDK4I, CDKN2, CMM2, INK4, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of CDKN2A

  • Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers [1].
  • High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families [2].
  • Six CDKN2A families had pancreatic cancer [3].
  • They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer [2].
  • We previously described CDKN2A exon 2 mutations in a pilot study of 43 esophageal cancers [4].
  • Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer [5].
  • The p16INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P<0.0043) and SDHB mutation (P<0.002). p16INK4A mRNA expression showed moderate suppression in malignant cases (P<0.05) [6].

Psychiatry related information on CDKN2A


High impact information on CDKN2A


Chemical compound and disease context of CDKN2A


Biological context of CDKN2A

  • Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression [22].
  • We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer [22].
  • Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa [22].
  • We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types [2].
  • The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture [23].

Anatomical context of CDKN2A

  • Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A [23].
  • Microsatellite analysis revealed that the majority of these cell lines were hemi/homozygous for the region surrounding CDKN2A, indicating that the wild-type allele had been lost [24].
  • CDKN2A is homozygously deleted or mutated in a large proportion of tumor cell lines and some primary tumors, including melanomas [24].
  • 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 [25].
  • Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells [26].

Associations of CDKN2A with chemical compounds

  • Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3) [3].
  • Treatment of cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methyltransferase 1, induced a dose and duration dependent increased expression of both p16(INK4a) and p19(INK4d), the products of CDKN2A and CDKN2D, respectively [27].
  • Flow cytometry on primary CVX and NCK and immunohistochemical staining of formalin fixed paraffin-embedded tumor specimens from which primary CVX cultures were derived as well as from a separate set of invasive cervical cancers confirmed differential expression of the CDKN2A/p16 and PTGES markers on CVX versus NCK [28].
  • Serial studies of methylation of CDKN2B and CDKN2A in relapsed acute promyelocytic leukaemia treated with arsenic trioxide [29].
  • DESIGN AND METHODS: CDKN2A inactivation by deletion or methylation was studied using gene dosage and methyl-specific polymerase chain reaction [30].
  • The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-beta2, estrogen receptor-alpha, and breast cancer-associated 1 genes (P = 0.001) [31].

Physical interactions of CDKN2A


Enzymatic interactions of CDKN2A


Regulatory relationships of CDKN2A

  • Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53 [41].
  • Distinct E2F-mediated transcriptional program regulates p14ARF gene expression [42].
  • We found that E2F1 overexpression leads to an inhibition of cyclin D1-dependent kinase activity and induces the expression of a p16-related transcript [43].
  • In this study we show that p16INK4a is expressed in cervical cancer cell lines in which the RB gene, Rb, is not functional, either as a consequence of Rb mutation or expression of the human papillomavirus E7 protein [43].
  • Lastly, transcription from the ARF promoter was down-regulated by wild-type p53 expression, and the magnitude of the effect correlated with the status of the endogenous p53 gene [44].

Other interactions of CDKN2A


Analytical, diagnostic and therapeutic context of CDKN2A


  1. Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Liu, L., Dilworth, D., Gao, L., Monzon, J., Summers, A., Lassam, N., Hogg, D. Nat. Genet. (1999) [Pubmed]
  2. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M., Måsbäck, A., Westerdahl, J., Olsson, H., Ingvar, C. J. Natl. Cancer Inst. (2000) [Pubmed]
  3. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. Goldstein, A.M., Struewing, J.P., Chidambaram, A., Fraser, M.C., Tucker, M.A. J. Natl. Cancer Inst. (2000) [Pubmed]
  4. Intragenic mutations of CDKN2B and CDKN2A in primary human esophageal cancers. Suzuki, H., Zhou, X., Yin, J., Lei, J., Jiang, H.Y., Suzuki, Y., Chan, T., Hannon, G.J., Mergner, W.J., Abraham, J.M. Hum. Mol. Genet. (1995) [Pubmed]
  5. Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians. Chen, J., Li, D., Wei, C., Sen, S., Killary, A.M., Amos, C.I., Evans, D.B., Abbruzzese, J.L., Frazier, M.L. Clin. Cancer Res. (2007) [Pubmed]
  6. Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas. Kiss, N.B., Geli, J., Lundberg, F., Avci, C., Velazquez-Fernandez, D., Hashemi, J., Weber, G., Höög, A., Ekström, T.J., Bäckdahl, M., Larsson, C. Endocr. Relat. Cancer (2008) [Pubmed]
  7. Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease. Arendt, T., Holzer, M., Gärtner, U. Journal of neural transmission (Vienna, Austria : 1996) (1998) [Pubmed]
  8. Promotor hypermethylation of p14ARF is a key alteration for progression of oral squamous cell carcinoma. Ishida, E., Nakamura, M., Ikuta, M., Shimada, K., Matsuyoshi, S., Kirita, T., Konishi, N. Oral Oncol. (2005) [Pubmed]
  9. Role for PP2A in ARF signaling to p53. Moule, M.G., Collins, C.H., McCormick, F., Fried, M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Belinsky, S.A., Palmisano, W.A., Gilliland, F.D., Crooks, L.A., Divine, K.K., Winters, S.A., Grimes, M.J., Harms, H.J., Tellez, C.S., Smith, T.M., Moots, P.P., Lechner, J.F., Stidley, C.A., Crowell, R.E. Cancer Res. (2002) [Pubmed]
  11. Induction of Id1 and Id3 by latent membrane protein 1 of Epstein-Barr virus and regulation of p27/Kip and cyclin-dependent kinase 2 in rodent fibroblast transformation. Everly, D.N., Mainou, B.A., Raab-Traub, N. J. Virol. (2004) [Pubmed]
  12. The Regulation of INK4/ARF in Cancer and Aging. Kim, W.Y., Sharpless, N.E. Cell (2006) [Pubmed]
  13. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Chudnovsky, Y., Adams, A.E., Robbins, P.B., Lin, Q., Khavari, P.A. Nat. Genet. (2005) [Pubmed]
  14. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Graux, C., Cools, J., Melotte, C., Quentmeier, H., Ferrando, A., Levine, R., Vermeesch, J.R., Stul, M., Dutta, B., Boeckx, N., Bosly, A., Heimann, P., Uyttebroeck, A., Mentens, N., Somers, R., MacLeod, R.A., Drexler, H.G., Look, A.T., Gilliland, D.G., Michaux, L., Vandenberghe, P., Wlodarska, I., Marynen, P., Hagemeijer, A. Nat. Genet. (2004) [Pubmed]
  15. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Robert, M.F., Morin, S., Beaulieu, N., Gauthier, F., Chute, I.C., Barsalou, A., MacLeod, A.R. Nat. Genet. (2003) [Pubmed]
  16. Multiple tumor suppressor pathways negatively regulate telomerase. Lin, S.Y., Elledge, S.J. Cell (2003) [Pubmed]
  17. CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas. Hashemi, J., Platz, A., Ueno, T., Stierner, U., Ringborg, U., Hansson, J. Cancer Res. (2000) [Pubmed]
  18. Overexpression of a fish CDKN2 gene in a hereditary melanoma model. Kazianis, S., Coletta, L.D., Morizot, D.C., Johnston, D.A., Osterndorff, E.A., Nairn, R.S. Carcinogenesis (2000) [Pubmed]
  19. Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours. Schmidt, E.E., Ichimura, K., Messerle, K.R., Goike, H.M., Collins, V.P. Br. J. Cancer (1997) [Pubmed]
  20. Cloning and characterization of the CDKN2A and p19ARF genes from Monodelphis domestica. Sherburn, T.E., Gale, J.M., Ley, R.D. DNA Cell Biol. (1998) [Pubmed]
  21. The role of p16 in the E2F-dependent thymidine kinase regulation. Hengstschläger, M., Hengstschläger-Ottnad, E., Pusch, O., Wawra, E. Oncogene (1996) [Pubmed]
  22. Evolution of neoplastic cell lineages in Barrett oesophagus. Barrett, M.T., Sanchez, C.A., Prevo, L.J., Wong, D.J., Galipeau, P.C., Paulson, T.G., Rabinovitch, P.S., Reid, B.J. Nat. Genet. (1999) [Pubmed]
  23. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P.A., Lomax, M., James, M.C., Vatcheva, R., Bates, S., Vousden, K.H., Parry, D., Gruis, N., Smit, N., Bergman, W., Peters, G. EMBO J. (2002) [Pubmed]
  24. CDKN2A/p16 is inactivated in most melanoma cell lines. Castellano, M., Pollock, P.M., Walters, M.K., Sparrow, L.E., Down, L.M., Gabrielli, B.G., Parsons, P.G., Hayward, N.K. Cancer Res. (1997) [Pubmed]
  25. Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Vance, K.W., Carreira, S., Brosch, G., Goding, C.R. Cancer Res. (2005) [Pubmed]
  26. CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. Nielsen, G.P., Burns, K.L., Rosenberg, A.E., Louis, D.N. Am. J. Pathol. (1998) [Pubmed]
  27. Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells. Zhu, W.G., Dai, Z., Ding, H., Srinivasan, K., Hall, J., Duan, W., Villalona-Calero, M.A., Plass, C., Otterson, G.A. Oncogene (2001) [Pubmed]
  28. Gene expression profiles of primary HPV16- and HPV18-infected early stage cervical cancers and normal cervical epithelium: identification of novel candidate molecular markers for cervical cancer diagnosis and therapy. Santin, A.D., Zhan, F., Bignotti, E., Siegel, E.R., Cané, S., Bellone, S., Palmieri, M., Anfossi, S., Thomas, M., Burnett, A., Kay, H.H., Roman, J.J., O'Brien, T.J., Tian, E., Cannon, M.J., Shaughnessy, J., Pecorelli, S. Virology (2005) [Pubmed]
  29. Serial studies of methylation of CDKN2B and CDKN2A in relapsed acute promyelocytic leukaemia treated with arsenic trioxide. Au, W.Y., Fung, A.T., Ma, E.S., Chan, C.H., Wong, K.F., Chim, C.S., Liang, R.H., Kwong, Y.L. Br. J. Haematol. (2005) [Pubmed]
  30. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Mirebeau, D., Acquaviva, C., Suciu, S., Bertin, R., Dastugue, N., Robert, A., Boutard, P., Méchinaud, F., Plouvier, E., Otten, J., Vilmer, E., Cavé, H. Haematologica (2006) [Pubmed]
  31. Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF. Bean, G.R., Bryson, A.D., Pilie, P.G., Goldenberg, V., Baker, J.C., Ibarra, C., Brander, D.M., Paisie, C., Case, N.R., Gauthier, M., Reynolds, P.A., Dietze, E., Ostrander, J., Scott, V., Wilke, L.G., Yee, L., Kimler, B.F., Fabian, C.J., Zalles, C.M., Broadwater, G., Tlsty, T.D., Seewaldt, V.L. Clin. Cancer Res. (2007) [Pubmed]
  32. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Zhang, Y., Xiong, Y., Yarbrough, W.G. Cell (1998) [Pubmed]
  33. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. Parry, D., Bates, S., Mann, D.J., Peters, G. EMBO J. (1995) [Pubmed]
  34. Cyclin E, a redundant cyclin in breast cancer. Gray-Bablin, J., Zalvide, J., Fox, M.P., Knickerbocker, C.J., DeCaprio, J.A., Keyomarsi, K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  35. Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma. Easton, J., Wei, T., Lahti, J.M., Kidd, V.J. Cancer Res. (1998) [Pubmed]
  36. Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Powell, E.L., Leoni, L.M., Canto, M.I., Forastiere, A.A., Iocobuzio-Donahue, C.A., Wang, J.S., Maitra, A., Montgomery, E. Am. J. Surg. Pathol. (2005) [Pubmed]
  37. Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured melanoma cells. Rizos, H., Darmanian, A.P., Indsto, J.O., Shannon, J.A., Kefford, R.F., Mann, G.J. Melanoma Res. (1999) [Pubmed]
  38. Caspase 3 specifically cleaves p21WAF1/CIP1 in the earlier stage of apoptosis in SK-HEP-1 human hepatoma cells. Park, J.A., Kim, K.W., Kim, S.I., Lee, S.K. Eur. J. Biochem. (1998) [Pubmed]
  39. Molecular genetic analysis of phosphatase and tensin homolog and p16 tumor suppressor genes in patients with malignant glioma. Abdullah, J.M., Zainuddin, N., Sulong, S., Jaafar, H., Isa, M.N. Neurosurgical focus [electronic resource]. (2003) [Pubmed]
  40. Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo. Xirodimas, D., Saville, M.K., Edling, C., Lane, D.P., Laín, S. Oncogene (2001) [Pubmed]
  41. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Zhang, Y., Xiong, Y. Mol. Cell (1999) [Pubmed]
  42. Distinct E2F-mediated transcriptional program regulates p14ARF gene expression. Komori, H., Enomoto, M., Nakamura, M., Iwanaga, R., Ohtani, K. EMBO J. (2005) [Pubmed]
  43. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Khleif, S.N., DeGregori, J., Yee, C.L., Otterson, G.A., Kaye, F.J., Nevins, J.R., Howley, P.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  44. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Robertson, K.D., Jones, P.A. Mol. Cell. Biol. (1998) [Pubmed]
  45. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Russo, A.A., Tong, L., Lee, J.O., Jeffrey, P.D., Pavletich, N.P. Nature (1998) [Pubmed]
  46. Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon. Bartkova, J., Thullberg, M., Slezak, P., Jaramillo, E., Rubio, C., Thomassen, L.H., Bartek, J. Gastroenterology (2001) [Pubmed]
  47. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Alcorta, D.A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., Barrett, J.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  48. Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL. Cobbers, J.M., Wolter, M., Reifenberger, J., Ring, G.U., Jessen, F., An, H.X., Niederacher, D., Schmidt, E.E., Ichimura, K., Floeth, F., Kirsch, L., Borchard, F., Louis, D.N., Collins, V.P., Reifenberger, G. Brain Pathol. (1998) [Pubmed]
  49. Patterns of CDKN2A gene loss in sequential oral epithelial dysplasias and carcinomas. Shahnavaz, S.A., Bradley, G., Regezi, J.A., Thakker, N., Gao, L., Hogg, D., Jordan, R.C. Cancer Res. (2001) [Pubmed]
  50. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Illei, P.B., Rusch, V.W., Zakowski, M.F., Ladanyi, M. Clin. Cancer Res. (2003) [Pubmed]
WikiGenes - Universities