CDKN2A

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CDKN2A

cyclin-dependent kinase inhibitor 2A

Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform 6 may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.

Publications (36)

Dysphagia as a major symptom of tetanus. Ross J, Murrant NJ. The Journal of laryngology and otology. 1992 106:923-4. (ICC, WB; Mouse) [PubMed:1474320]

Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Khan SH, Moritsugu J, Wahl GM. Proceedings of the National Academy of Sciences of the United States of America. 2000 97:3266-71. (WB; Mouse) [PubMed:10716710] [PMC:PMC16227]

Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ. Science (New York, N.Y.). 2000 288:870-4. [PubMed:10797012]

Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation. Lin AW, Lowe SW. Proceedings of the National Academy of Sciences of the United States of America. 2001 98:5025-30. (ICC, WB; Mouse) [PubMed:11309506] [PMC:PMC33157]

The p14ARF tumor suppressor protein facilitates nucleolar sequestration of hypoxia-inducible factor-1alpha (HIF-1alpha ) and inhibits HIF-1-mediated transcription. Fatyol K, Szalay AA. The Journal of biological chemistry. 2001 276:28421-9. (WB; Mouse, Human) [PubMed:11382768]

Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA. Nature. 2001 413:86-91. [PubMed:11544531]

Hepatitis B virus X protein differentially regulates cell cycle progression in X-transforming versus nontransforming hepatocyte (AML12) cell lines. Lee S, Tarn C, Wang WH, Chen S, Hullinger RL, Andrisani OM. The Journal of biological chemistry. 2002 277:8730-40. (WB; Mouse) [PubMed:11756437]

Role of the alternating reading frame (P19)-p53 pathway in an in vivo murine colon tumor model. Nambiar PR, Giardina C, Guda K, Aizu W, Raja R, Rosenberg DW. Cancer research. 2002 62:3667-74. (IHC-Fr; Mouse) [PubMed:12097273]

Macrophage migration inhibitory factor deficiency is associated with altered cell growth and reduced susceptibility to Ras-mediated transformation. Petrenko O, Fingerle-Rowson G, Peng T, Mitchell RA, Metz CN. The Journal of biological chemistry. 2003 278:11078-85. (WB; Mouse) [PubMed:12538581]

Absence of p53 complements defects in Abelson murine leukemia virus signaling. Unnikrishnan I, Rosenberg N. Journal of virology. 2003 77:6208-15. (WB; Mouse) [PubMed:12743277] [PMC:PMC155034]

The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH, DePinho RA. Oncogene. 2004 23:379-85. (WB; Mouse) [PubMed:14724566]

Active Akt and functional p53 modulate apoptosis in Abelson virus-transformed pre-B cells. Gong L, Unnikrishnan I, Raghavan A, Parmar K, Rosenberg N. Journal of virology. 2004 78:1636-44. [PubMed:14747529] [PMC:PMC369499]

p16(Ink4a) interferes with Abelson virus transformation by enhancing apoptosis. Sachs Z, Sharpless NE, DePinho RA, Rosenberg N. Journal of virology. 2004 78:3304-11. [PubMed:15016851] [PMC:PMC371071]

Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. Sun LQ, Lee DW, Zhang Q, Xiao W, Raabe EH, Meeker A, Miao D, Huso DL, Arceci RJ. Genes & development. 2004 18:1035-46. [PubMed:15105378] [PMC:PMC406293]

p19ARF determines the balance between normal cell proliferation rate and apoptosis during mammary gland development. Yi Y, Shepard A, Kittrell F, Mulac-Jericevic B, Medina D, Said TK. Molecular biology of the cell. 2004 15:2302-11. (WB; Mouse) [PubMed:15105443] [PMC:PMC404024]

Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Aslanian A, Iaquinta PJ, Verona R, Lees JA. Genes & development. 2004 18:1413-22. [PubMed:15175242] [PMC:PMC423192]

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, Kumar R, Jenkins RB, de Groen PC, Roche P, van Deursen JM. Nature genetics. 2004 36:744-9. (WB; Mouse) [PubMed:15208629]

Sensitization to the lysosomal cell death pathway upon immortalization and transformation. Fehrenbacher N, Gyrd-Hansen M, Poulsen B, Felbor U, Kallunki T, Boes M, Weber E, Leist M, Jttel M. Cancer research. 2004 64:5301-10. (WB; Mouse) [PubMed:15289336]

N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ. Genes & development. 2004 18:1862-74. (WB; Mouse, Human) [PubMed:15289458] [PMC:PMC517406]

Resistance of CD1d-/- mice to ultraviolet-induced skin cancer is associated with increased apoptosis. Matsumura Y, Moodycliffe AM, Nghiem DX, Ullrich SE, Ananthaswamy HN. The American journal of pathology. 2004 165:879-87. [PubMed:15331412] [PMC:PMC1618602]

Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic A, van Deursen JM. The Journal of cell biology. 2006 172:529-40. [PubMed:16476774] [PMC:PMC2063673]

Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Miller SJ, Rangwala F, Williams J, Ackerman P, Kong S, Jegga AG, Kaiser S, Aronow BJ, Frahm S, Kluwe L, Mautner V, Upadhyaya M, Muir D, Wallace M, Hagen J, Quelle DE, Watson MA, Perry A, Gutmann DH, Ratner N. Cancer research. 2006 66:2584-91. (WB; Human) [PubMed:16510576]

Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex. Klochendler-Yeivin A, Picarsky E, Yaniv M. Molecular and cellular biology. 2006 26:2661-74. [PubMed:16537910] [PMC:PMC1430322]

E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop. Timmers C, Sharma N, Opavsky R, Maiti B, Wu L, Wu J, Orringer D, Trikha P, Saavedra HI, Leone G. Molecular and cellular biology. 2007 27:65-78. [PubMed:17167174] [PMC:PMC1800646]

The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J, Socci ND, Behrendt N, Ma L, Maki RG, Pandolfi PP, Cordon-Cardo C. Nature medicine. 2007 13:748-53. [PubMed:17496901]

A non-tumor suppressor role for basal p19ARF in maintaining nucleolar structure and function. Apicelli AJ, Maggi LB, Hirbe AC, Miceli AP, Olanich ME, Schulte-Winkeler CL, Saporita AJ, Kuchenreuther M, Sanchez J, Weilbaecher K, Weber JD. Molecular and cellular biology. 2008 28:1068-80. [PubMed:18070929] [PMC:PMC2223401]

The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma. Mascaux C, Bex F, Martin B, Burny A, Haller A, Paesmans M, Willard-Gallo K, Ninane V, Sculier JP. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2008 32:678-86. (IHC; Human) [PubMed:18480108]

Frequent p16-independent inactivation of p14ARF in human melanoma. Freedberg DE, Rigas SH, Russak J, Gai W, Kaplow M, Osman I, Turner F, Randerson-Moor JA, Houghton A, Busam K, Timothy Bishop D, Bastian BC, Newton-Bishop JA, Polsky D. Journal of the National Cancer Institute. 2008 100:784-95. (IHC; Human) [PubMed:18505964]

Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis. Wang WH, Hullinger RL, Andrisani OM. The Journal of biological chemistry. 2008 283:25455-67. (WB; Mouse) [PubMed:18606816] [PMC:PMC2533071]

mTORC1 promotes survival through translational control of Mcl-1. Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, Trojahn U, Wendel HG, Charest A, Bronson RT, Kogan SC, Nadon R, Housman DE, Lowe SW, Pelletier J. Proceedings of the National Academy of Sciences of the United States of America. 2008 105:10853-8. [PubMed:18664580] [PMC:PMC2504845]

Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Chen D, Shan J, Zhu WG, Qin J, Gu W. Nature. 2010 464:624-7. (IP; Human) [PubMed:20208519]

Reactivating the ARF-p53 axis in AML cells by targeting ULF. Chen D, Yoon JB, Gu W. Cell cycle (Georgetown, Tex.). 2010 9:2946-51. (IP; Human) [PubMed:20699639] [PMC:PMC3040923]

The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis. Muniz VP, Barnes JM, Paliwal S, Zhang X, Tang X, Chen S, Zamba KD, Cullen JJ, Meyerholz DK, Meyers S, Davis JN, Grossman SR, Henry MD, Quelle DE. Molecular cancer research : MCR. 2011 9:867-77. (WB; Mouse) [PubMed:21636682] [PMC:PMC3140613]

TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation. Chio II, Sasaki M, Ghazarian D, Moreno J, Done S, Ueda T, Inoue S, Chang YL, Chen NJ, Mak TW. Nature cell biology. 2012 14:625-33. (WB; Mouse, Human) [PubMed:22561347]

Role of deltaNp63(pos)CD44v(pos) cells in the development of N-nitroso-tris-chloroethylurea-induced peripheral-type mouse lung squamous cell carcinomas. Yamano S, Gi M, Tago Y, Doi K, Okada S, Hirayama Y, Tachibana H, Ishii N, Fujioka M, Tatsumi K, Wanibuchi H. Cancer science. 2016 February;107:123-32. (IHC; Mouse) [Full Text Article] [PubMed:26663681] [PMC:PMC4768398]

Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a<sup>. Lawrence I, Bene M, Nacarelli T, Azar A, Cohen JZ, Torres C, Johannes G, Sell C. GeroScience. 2018 April;40:193-199. [Full Text Article] [PubMed:29651745] [PMC:PMC5964056]

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Gene Name:	cyclin-dependent kinase inhibitor 2A
Synonyms:	CDKN2A, ARF, Cdk4 inhibitor, CDK4 inhibitor p16-INK4, INK4, INK4A, Multiple tumor suppressor 1, MTS-1, MTS1, p16-INK4, p16-INK4A, p16INK4, p19, p14, p16, p16 INK4A, p16INK4A, p14ARF, TP16, CDK4I, CDKN2, CMM2, MLM, p19ARF
Target Sequences:	NM_000077 NP_000068.1 P42771

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cyclin-dependent kinase inhibitor 2A

Publications (36)

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