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http://en.wikipedia.org/wiki/P16_(gene)

Cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
Image illustrative de l’article Tremis/Brouillon
PDB rendering based on 1a5e
Caractéristiques générales
Symbole P19Arf_N



Modèle:GNF Protein box


Modèle:PBB Modèle:Infobox protein family

Cyclin-dependent kinase inhibitor 2A, (CDKN2A, p16Ink4A) also known as multiple tumor suppressor 1 (MTS-1), is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene.[1],[2],[3] P16 plays an important role in regulating the cell cycle, and mutations in p16 increase the risk of developing a variety of cancers, notably melanoma.

Function[modifier | modifier le code]

This gene generates several transcript variants which 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 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This 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.[4] In spite of the 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 cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.[1]

Increased expression of the p16 gene as organisms age reduces the proliferation of stem cells.[5] This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.

Clinical significance[modifier | modifier le code]

Mutations in 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.[6],[7] Examples include:

Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene.[8][9][10]

Homozygous deletion of p16 are frequently found in esophageal cancer and gastric cancer cell lines.[11]

Concentrations of p16INK4a increase dramatically as tissue ages. Therefore p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.[12]

Interactions[modifier | modifier le code]

P16 (gene) has been shown to interact with SERTAD1[13],[14] CCNG1[15] Death associated protein 6[16] P53[17],[18],[19] E4F1[18] Cyclin-dependent kinase 4[13],[14],[20],[21],[22],[23] Cyclin-dependent kinase 6[21],[24],[25] Mdm2[16],[17],[19],[26],[27] RPL11[17] and PPP1R9B.[28]

References[modifier | modifier le code]

  1. ↑ a et b « Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) »
  2. ↑ Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K et Carson DA, « Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers », Nature, vol. 368, no 6473,‎ , p. 753–6 (PMID 8152487, DOI 10.1038/368753a0)
  3. ↑ Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G et Kamb A, « Complex structure and regulation of the P16 (MTS1) locus », Cancer Res., vol. 55, no 14,‎ , p. 2988–94 (PMID 7606716, lire en ligne)
  4. ↑ "Molecular biology of cancer", Oxford University Press, 2005, (ISBN 978-0-19-926472-8), Section 5.3
  5. ↑ Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S et Sharpless NE, « p16INK4a induces an age-dependent decline in islet regenerative potential », Nature, vol. 443, no 7110,‎ , p. 453–7 (PMID 16957737, DOI 10.1038/nature05092)
  6. ↑ Liggett WH et Sidransky D, « Role of the p16 tumor suppressor gene in cancer », J. Clin. Oncol., vol. 16, no 3,‎ , p. 1197–206 (PMID 9508208, lire en ligne)
  7. ↑ Rocco JW et Sidransky D, « p16(MTS-1/CDKN2/INK4a) in cancer progression », Exp. Cell Res., vol. 264, no 1,‎ , p. 42–55 (PMID 11237522, DOI 10.1006/excr.2000.5149)
  8. ↑ Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH et Yeo CJ, « Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma », Nat. Genet., vol. 8, no 1,‎ , p. 27–32 (PMID 7726912, DOI 10.1038/ng0994-27)
  9. ↑ Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA et Goodfellow PJ, « Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas », Genes Chromosomes Cancer, vol. 14, no 3,‎ , p. 189–95 (PMID 8589035, DOI 10.1002/gcc.2870140306)
  10. ↑ Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins R et Hogg D, « Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma », Oncogene, vol. 11, no 2,‎ , p. 405–12 (PMID 7624155)
  11. ↑ Igaki H, Sasaki H, Kishi T, Sakamoto H, Tachimori Y, Kato H, Watanabe H, Sugimura T et Terada M, « Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines », Biochem. Biophys. Res. Commun., vol. 203, no 2,‎ , p. 1090–5 (PMID 8093026, DOI 10.1006/bbrc.1994.2294)
  12. ↑ Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE et Sharpless NE, « Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging », Aging Cell, vol. 8, no 4,‎ , p. 439–48 (PMID 19485966, PMCID 2752333, DOI 10.1111/j.1474-9726.2009.00489.x)
  13. ↑ a et b Melvin W Scott, , Tsai Ming-Daw, Muscarella Peter, Ming-Daw Tsai et Peter Muscarella, « The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner », Biochemistry, United States, vol. 43, no 14,‎ , p. 4394–9 (ISSN 0006-2960, PMID 15065884, DOI 10.1021/bi035601s)
  14. ↑ a et b Nakamura T, Ohtani N, Hampson L, Hampson I N, Shimamoto A, Furuichi Y, Okumura K, Niwa S et Taya Y, « Regulation of CDK4 activity by a novel CDK4-binding protein, p34SEI-1 », Genes Dev., UNITED STATES, vol. 13, no 22,‎ , p. 3027–33 (ISSN 0890-9369, PMID 10580009, PMCID 317153, DOI 10.1101/gad.13".3027)
  15. ↑ Samuels Tina, Winckler Sarah, Korgaonkar Chandrashekhar, Tompkins Van, Horne Mary C, , Quelle Dawn E et DE Quelle, « Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways », Mol. Cancer Res., United States, vol. 1, no 3,‎ , p. 195–206 (ISSN 1541-7786, PMID 12556559)
  16. ↑ a et b Mondal Soma, , Rutka James T et James T. Rutka, « p14ARF interacts with DAXX: effects on HDM2 and p53 », Cell Cycle, United States, vol. 7, no 12,‎ , p. 1836–50 (PMID 18583933, DOI 10.4161/cc.7.12.6025)
  17. ↑ a b et c Wolf Gabrielle White, Bhat Krishna, Jin Aiwen, Allio Theresa, Burkhart William A, , Xiong Yue et Y. Xiong, « Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway », Mol. Cell. Biol., United States, vol. 23, no 23,‎ , p. 8902–12 (ISSN 0270-7306, PMID 14612427, PMCID 262682, DOI 10.1128/MCB.23.23.8902-8912.2003)
  18. ↑ a et b Diefenbach Eve, Badhwar Prerna, Woodruff Sarah, Becker Therese M, Rooney Robert J, , Kefford Richard F et RF Kefford, « Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition », J. Biol. Chem., United States, vol. 278, no 7,‎ , p. 4981–9 (ISSN 0021-9258, PMID 12446718, DOI 10.1074/jbc.M210978200)
  19. ↑ a et b Xiong Y, , Yarbrough W G et Wendell G Yarbrough, « ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways », Cell, UNITED STATES, vol. 92, no 6,‎ , p. 725–34 (ISSN 0092-8674, PMID 9529249, DOI 10.1016/S0092-8674(00)81401-4)
  20. ↑ Chu Peter, Elisma Fred, Li Hongyan, Taylor Paul, Climie Shane, McBroom-Cerajewski Linda, Robinson Mark D, Connor Liam et Li Michael, « Large-scale mapping of human protein–protein interactions by mass spectrometry », Mol. Syst. Biol., England, vol. 3, no 1,‎ , p. 89 (PMID 17353931, PMCID 1847948, DOI 10.1038/msb4100134)
  21. ↑ a et b Paramio J M, Ball K L, Laín S, , Lane D P et David P. Lane, « Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A », Curr. Biol., ENGLAND, vol. 6, no 1,‎ , p. 84–91 (ISSN 0960-9822, PMID 8805225, DOI 10.1016/S0960-9822(02)00425-6)
  22. ↑ Hannon G J, , Beach D et David Beach, « A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 », Nature, ENGLAND, vol. 366, no 6456,‎ , p. 704–7 (ISSN 0028-0836, PMID 8259215, DOI 10.1038/366704a0)
  23. ↑ Wautlet B S, Morrissey D, Mulheron J, Sedman S A, Brinkley P, Price S, , Webster K R et KR Webster, « Identification of CDK4 sequences involved in cyclin D1 and p16 binding », J. Biol. Chem., UNITED STATES, vol. 272, no 30,‎ , p. 18869–74 (ISSN 0021-9258, PMID 9228064, DOI 10.1074/jbc'2.30.18869)
  24. ↑ Tong L, Lee J O, Jeffrey P D, , Pavletich N P et Philip D. Jeffrey, « Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a », Nature, ENGLAND, vol. 395, no 6699,‎ , p. 237–43 (ISSN 0028-0836, PMID 9751050, DOI 10.1038/26155)
  25. ↑ Ojala P M, Tong L, Mäkelä T P, , Solomon M J et MJ Solomon, « CAK-independent Activation of CDK6 by a Viral Cyclin », Mol. Biol. Cell, United States, vol. 12, no 12,‎ , p. 3987–99 (ISSN 1059-1524, PMID 11739795, PMCID 60770)
  26. ↑ Llanos Susana, , Peters Gordon et Gordon Peters, « Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2 », Oncogene, England, vol. 21, no 29,‎ , p. 4498–507 (ISSN 0950-9232, PMID 12085228, DOI 10.1038/sj.onc.1205558)
  27. ↑ Schreiber-Agus N, Liégeois N J, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I et Lee H W, « The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 », Cell, UNITED STATES, vol. 92, no 6,‎ , p. 713–23 (ISSN 0092-8674, PMID 9529248, DOI 10.1016/S0092-8674(00)81400-2)
  28. ↑ Calogero R A, Sansone F, Calabrò V, Parisi T, Borrelli L, Saviozzi S, , La Mantia G et G La Mantia, « The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein », J. Biol. Chem., United States, vol. 276, no 17,‎ , p. 14161–9 (ISSN 0021-9258, PMID 11278317, DOI 10.1074/jbc.M006845200)

Further reading[modifier | modifier le code]

  • Smith-Sørensen B et Hovig E, « CDKN2A (p16INK4A) somatic and germline mutations », Hum. Mutat., vol. 7, no 4,‎ , p. 294–303 (PMID 8723678, DOI 10.1002/(SICI)1098-1004(1996)7:4<294::AID-HUMU2>3.0.CO;2-9)
  • Dracopoli NC et Fountain JW, « CDKN2 mutations in melanoma », Cancer Surv., vol. 26,‎ , p. 115–32 (PMID 8783570)
  • Akita H, « [Prognostic importance of altered expression of cell cycle regulators in lung cancer] », Nippon Rinsho, vol. 60 Suppl 5,‎ , p. 267–71 (PMID 12101670)
  • Kusy S, Larsen CJ et Roche J, « p14ARF, p15INK4b and p16INK4a methylation status in chronic myelogenous leukemia », Leuk. Lymphoma, vol. 45, no 10,‎ , p. 1989–94 (PMID 15370242, DOI 10.1080/10428190410001714025)
  • Gjerset RA, « DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer », J. Mol. Histol., vol. 37, nos 5–7,‎ , p. 239–51 (PMID 16855788, DOI 10.1007/s10735-006-9040-y)
  • Yildiz IZ, Usubütün A, Firat P, A Ayhan et T Küçükali, « Efficiency of immunohistochemical p16 expression and HPV typing in cervical squamous intraepithelial lesion grading and review of the p16 literature », Pathol. Res. Pract., vol. 203, no 6,‎ , p. 445–9 (PMID 17543474, DOI 10.1016/j.prp.2007.03.010)

External links[modifier | modifier le code]

{{PDB Gallery|geneid=1029}} {{Cell cycle proteins}} {{Tumor suppressor genes}} [[Catégorie:Tumor suppressor genes]] [[es:P16]] [[ja:P16]] [[fi:P16]] [[en:P16_(gene)]]

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