| Written | 2004-08 | Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire |
| Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France | ||
| Updated | 2007-08 | Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire |
| Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France |
| Identity |
| Alias_names | CDKN2 |
| MLM | |
| cyclin-dependent kinase inhibitor 2A (melanoma | |
| Alias_symbol (synonym) | CDK4I |
| p16 | |
| INK4a | |
| MTS1 | |
| CMM2 | |
| ARF | |
| p19 | |
| p14 | |
| INK4 | |
| p16INK4a | |
| p19Arf | |
| p14ARF | |
| Other alias | CDKN2a |
| p16- INK4a | |
| TP16 | |
| HGNC (Hugo) | CDKN2A |
| LocusID (NCBI) | 1029 |
| Atlas_Id | 146 |
| Location | 9p21.3 [Link to chromosome band 9p21] |
| Location_base_pair | Starts at 21967752 and ends at 21975133 bp from pter ( according to hg19-Feb_2009) [Mapping CDKN2A.png] |
 | |
| Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics | |
| Fusion genes (updated 2016) | ADAMTSL1 (9p22.2) / CDKN2A (9p21.3) | CDKN2A (9p21.3) / CDKN2A (9p21.3) | CDKN2A (9p21.3) / CDKN2B (9p21.3) |
| CDKN2A (9p21.3) / CDKN2B-AS1 (9p21.3) | CDKN2A (9p21.3) / FAM230A (22q11.21) | CDKN2A (9p21.3) / FOCAD (9p21.3) | |
| CDKN2A (9p21.3) / MGA (15q15.1) | CDKN2A (9p21.3) / MTAP (9p21.3) | CDKN2A (9p21.3) / SRGAP2 (1q32.1) | |
| FOCAD (9p21.3) / CDKN2A (9p21.3) | Ig () / CDKN2A (9p21.3) | MGA (15q15.1) / CDKN2A (9p21.3) | |
| MTAP (9p21.3) / CDKN2A (9p21.3) | TRA () / CDKN2A (9p21.3) |
| DNA/RNA |
| Description | The gene encompasses 6.6 kb of DNA; 3 exons. |
| Transcription | 471 nucleotides mRNA. The CDKN2 gene generates several transcript variants from different promoters. Each transcript differs in its first exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16-INK4 transcript. A putative DNA replication origin has been identified in close proximity of INK4/Arf locus that appears to transcriptionally repress p16 in a manner dependent on CDC6. |
| Protein |
| Description | 156 amino acids; 16.5 kDa protein. |
| Expression | Moderately expressed in many organs as thymus, liver, pancreas, prostate, lung, or kidney. |
| Function | P16-INK4a interacts strongly with cyclin-dependent kinase 4 and cyclin-dependent kinase 6 and inhibits their ability to interact with cyclins D. P16-INK4a induces cell cycle arrest at G1 and G2/M checkpoints, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle. P16-INK4a could act as a negative regulator of normal cells proliferation. |
| Homology | Belongs to the cdkn2 cyclin-dependent kinase inhibitor family. |
| Implicated in |
| Note | |
| Entity | Cutaneous malignant melanoma 2 (CMM2) |
| Disease | Malignant melanoma arises de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites. |
| Oncogenesis | Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait. CDKN2a has been identified as a major susceptibility gene for melanoma. However this gene accounts for a minority of familial melanoma. P16 is functionally inactivated by mutations or deletions, however, because many such mutations occur in exon 2, they can potentially also affect the alternative reading frame (ARF) protein. |
| Entity | Familial atypical multiple mole melanoma carcinoma syndrome (FAMMM) |
| Disease | Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer. |
| Oncogenesis | FAMMM syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Germline mutations in the p16-INK4a gene were found in approximately 40% of the FAMMM syndrome. |
| Entity | Sporadic cancer |
| Disease | Defects in CDKN2a are involved in tumor formation in a wide range of tissues. |
| Prognosis | Aberrant p16 expression is associated with more aggressive behavior. |
| Oncogenesis | LOH on 9p21 is one of the most frequent genetic alterations identified in human cancer. However, point mutations of p16 on the other chromosome are relatively rare. Promoter methylation appears as the commonest mechanism of p16 gene inactivation. |
| Entity | Aging |
| Note | Expression of p16 increases markedly with aging in many human tissues. This finding has led to the proposal that p16 expression could be used as a biomarker of physiologic, as opposed to chronologic, age. It was suggested that an age-induced increase in p16 expression contributes to the decline of replicative potential of certain self-renewing compartments with aging. |
| Bibliography |
| Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. |
| Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ |
| Genes, chromosomes & cancer. 1995 ; 14 (3) : 189-195. |
| PMID 8589035 |
| Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. |
| Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W |
| Nature genetics. 1995 ; 11 (2) : 210-212. |
| PMID 7550353 |
| Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. |
| Cowan JM, Halaban R, Francke U |
| Journal of the National Cancer Institute. 1988 ; 80 (14) : 1159-1164. |
| PMID 3166071 |
| FAMMM syndrome: pathogenesis and management. |
| Czajkowski R, Placek W, Drewa G, Czajkowska A, Uchańska G |
| Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2004 ; 30 (2 Pt 2) : 291-296. |
| PMID 14871223 |
| The CDKN2A (p16) gene and human cancer. |
| Foulkes WD, Flanders TY, Pollock PM, Hayward NK |
| Molecular medicine (Cambridge, Mass.). 1997 ; 3 (1) : 5-20. |
| PMID 9132280 |
| Oncogenic activity of Cdc6 through repression of the INK4/ARF locus. |
| Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M |
| Nature. 2006 ; 440 (7084) : 702-706. |
| PMID 16572177 |
| Germline p16 mutations in familial melanoma. |
| Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC |
| Nature genetics. 1994 ; 8 (1) : 15-21. |
| PMID 7987387 |
| A cell cycle regulator potentially involved in genesis of many tumor types. |
| Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH |
| Science (New York, N.Y.). 1994 ; 264 (5157) : 436-440. |
| PMID 8153634 |
| Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. |
| Koh J, Enders GH, Dynlacht BD, Harlow E |
| Nature. 1995 ; 375 (6531) : 506-510. |
| PMID 7777061 |
| Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. |
| Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A |
| Nature. 2001 ; 413 (6851) : 83-86. |
| PMID 11544530 |
| p16INK4a induces an age-dependent decline in islet regenerative potential. |
| Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE |
| Nature. 2006 ; 443 (7110) : 453-457. |
| PMID 16957737 |
| Methylation and p16: suppressing the suppressor. |
| Little M, Wainwright B |
| Nature medicine. 1995 ; 1 (7) : 633-634. |
| PMID 7585141 |
| 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. |
| Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D |
| Nature medicine. 1995 ; 1 (7) : 686-692. |
| PMID 7585152 |
| Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. |
| Quelle DE, Cheng M, Ashmun RA, Sherr CJ |
| Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (2) : 669-673. |
| PMID 9012842 |
| Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. |
| Quelle DE, Zindy F, Ashmun RA, Sherr CJ |
| Cell. 1995 ; 83 (6) : 993-1000. |
| PMID 8521522 |
| A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. |
| Serrano M, Hannon GJ, Beach D |
| Nature. 1993 ; 366 (6456) : 704-707. |
| PMID 8259215 |
| Role of the INK4a locus in tumor suppression and cell mortality. |
| Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA |
| Cell. 1996 ; 85 (1) : 27-37. |
| PMID 8620534 |
| The INK4a/ARF locus and melanoma. |
| Sharpless E, Chin L |
| Oncogene. 2003 ; 22 (20) : 3092-3098. |
| PMID 12789286 |
| 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 (6851) : 86-91. |
| PMID 11544531 |
| Complex structure and regulation of the P16 (MTS1) locus. |
| Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A |
| Cancer research. 1995 ; 55 (14) : 2988-2994. |
| PMID 7606716 |
| Citation |
| This paper should be referenced as such : |
| Saffroy, R ; Lemoine, A ; Debuire, B |
| CDKN2a (cyclin dependent kinase 2a / p16) |
| Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):89-90. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/CDKN2aID146.html |
| History of this paper: |
| Saffroy, R ; Lemoine, A ; Debuire, B. CDKN2a (cyclin dependent kinase 2a / p16). Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):280-281. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/38121/08-2004-CDKN2aID146.pdf |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 14 ] |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 38 ] |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 5 ] |
| Dysplastic nevus syndrome (DNS) Familial melanoma Hereditary pancreatic cancer Li-Fraumeni syndrome Melanoma-Astrocytoma syndrome |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:03:12 CEST 2017 |
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