Résumés
Résumé
La régulation transcriptionnelle de l’expression de p16INK4a constitue un pivot essentiel lors du vieillissement cellulaire et de la réponse à un stress, en particulier oncogénique. Cette régulation, complexe, implique des facteurs activateurs (protéines Ets1 et -2, protéine E47), dont la liaison sur le promoteur du gène INK4a peut être inhibée par les protéines Id-1 ou -4. L’inhibition transcriptionnelle de p16INK4a repose également sur le répresseur transcriptionnel Bmi1, ainsi que sur une régulation épigénétique complexe, dont le mécanisme est seulement partiellement connu : le promoteur et l’exon 1 de INK4a présentent tous deux un îlot CpG, qui peut être méthylé après qu’une méthylation de l’histone H3 et une désacétylation de l’histone H4 soient intervenues, tous ces événements participant à l’extinction du gène. À l’inverse, le gène INK4a serait protégé de la méthylation de ses ilôts CpG par l’hélicase A de l’ARN, et le remodelage chromatinien faisant intervenir le complexe SWI/SNF, antagoniste de Bmi1, activerait l’expression de INK4a. L’analyse de la complexité des différents mécanismes de régulation de INK4a et une meilleure compréhension des modulations épigénétiques de son expression devraient permettre de développer l’utilisation rationnelle de nouvelles stratégies thérapeutiques anticancéreuses.
Summary
The transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response. This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47. The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation. The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood. Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases. This DNA methylation is preceded by the lysine 9 histone H3 methylation and by the deacetylation of histone H4 both involved in gene silencing. Indeed, RNA Helicase A might protect INK4a against methylation of CpG island. Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression. The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents.
Parties annexes
Références
- 1. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclinD/CDK4. Nature 1993 ; 366 : 704-7.
- 2. Wolff B, Naumann M. INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB. Oncogene 1999 ; 18 : 2663-6.
- 3. Haas K, Staller P, Geisen C, et al. Mutual requirement of CDK4 and Myc in malignant transformation : evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc. Oncogene 1997 ; 10 : 179-92.
- 4. Serizawa H. Cyclin-dependent kinase inhibitor p16INK4A inhibits phosphorylation of RNA polymerase II by general transcription factor TFIIH. J Biol Chem 1998 ; 273 : 5427-30.
- 5. Nobori T, Miura K, Wu DJ, et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994 ; 368 : 753-6.
- 6. Merlo A, Herman JG, Mao L, et al. 5’pG island methylation is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995 ; 1 : 686-92
- 7. Sandig V, Brand K, Herwig S, et al. Adenovirally transferred p16INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumor cell death. Nat Med 1997 ; 3 : 313-9.
- 8. Kim M, Katayose Y, Rojanala L, et al. Induction of apoptosis in p16INK4A mutant cell lines by adenovirus-mediated overexpression of p16INK4A protein. Cell Death Differ 2000 ; 7 : 706-11.
- 9. Ausserlechner MJ, Obexer P, Geley S, et al. G1 arrest by p16INK4A uncouples growth from cell cycle progression in leukemia cells with deregulated cyclin E and c-Myc expression. Leukemia 2005 ; 19 : 1051-7.
- 10. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev 1999 ; 9 : 22-30
- 11. Hara E, Smith R, Parry D, et al. Regulation of p16CDKN2 expression and its implication for cell immortalization and senescence. Mol Cell Biol 1996 ; 16 : 859-67
- 12. Li Y, Nicolas MA, Shay JW, et al. Transcriptional repression of the D-type cyclin dependent kinase inhibitor p16 by retinoblastoma susceptibility gene product pRb. Cancer Res 1994 ; 54 : 6078-82.
- 13. Serrano M, Lin AW, McCurrach ME, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997 ; 88 : 593-602.
- 14. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53 : ARF-INK4a locus deletion impairs both the pRb and p53 tumor suppression pathways. Cell 1998 ; 92 : 725-34.
- 15. Shapiro GI, Edwards CD, Ewen ME, et al. p16ink4a participates in a G1 arrest checkpoint in response to DNA damage. Mol Cell Biol 1998 ; 18 : 378-87.
- 16. Krimpenfort P, Quon K.C, Mooi WJ, et al. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 2001 ; 413 : 83-6.
- 17. Serrano M, Lee H, Chin L, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996 ; 85 : 27-37.
- 18. Brookes S, Rowe J, Ruas M, et al. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 2002 ; 21 : 2936-45.
- 19. Drayton S, Rowe J, Jones R, et al. Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes. Cancer Cell 2003 ; 4 : 301-10
- 20. Gump J, Stokoe D, McCormick F. Phosphorylation of p16INK4A correlates with Cdk4 association. J Biol Chem 2003 ; 278 : 6619-22.
- 21. Mekki Y, Catallo R, Bertrand Y, et al. Enhanced expression of p16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Leukemia 1999 ; 13 : 181-9.
- 22. Zhu J, Woods D, McMahon M, et al. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 1998 ; 12 : 2997-3007.
- 23. Ohtani N, Zebedee Z, Huot TJG, et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 2001 ; 409 : 1067-70.
- 24. Ohtani N, Brennan P, Gaubatz S, et al. Epstein-Barr virus LMP1 blocks p16INK4a-pRb pathway by promoting nuclear export of E2F4/5. J Cell Biol 2003 ; 162 : 173-83.
- 25. Pagliuca A, Gallo P, De Luca P, et al. Class A helix-loop-helix proteins are positive regulators of several cyclin-dependent kinase inhibitors’ promoter activity and negatively affect cell growth. Cancer Res 2000 ; 60 : 1376-82
- 26. Zheng W, Wang H, Xue L, et al. Regulation of cellular senescence and p16INK4a expression by Id1 and E47 proteins in human diploid fibroblast. J Biol Chem 2004 ; 279 : 31524-32.
- 27. Hansson A, Manetopoulos C, Jönsson JI, et al. The basic helix-loop-helix transcription factor TAL1/SCL inhibits the expression of the p16INK4A and pT genes. Biochem Biophys Res Commun 2003 ; 312 : 1073-81.
- 28. Hara E, Yamaguchi T, Nojima H, et al. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J Biol Chem 1994 ; 269 : 2139-45.
- 29. Alani RM, Young AZ, Shifflett CB. Id1 regulation of cellular senescence through transcriptional repression of p16/INK4a. Proc Natl Acad Sci USA 2001 ; 98 : 7812-6.
- 30. Nickoloff BJ, Chaturvedi V, Bacon P, et al. Id-1 delays senescence but does not immortalize keratinocytes. J Biol Chem 2000 ; 275 : 27501-4.
- 31. Tang J, Gordon GM, Nickoloff BJ, et al. The helix-loop-helix protein Id-1 delays onset of replicative senescence in human endothelial cells. Lab Invest 2002 ; 82 : 1073-9.
- 32. Polsky D, Young AZ, Busam KJ, et al. The transcriptional repressor of p16INK4a, Id1, is up-regulated in early melanomas. Cancer Res 2001 ; 61 : 6008-11.
- 33. Pesce S, Benezra R. The loop region of the helix-loop-helix protein Id1 is critical for its dominant negative activity. Mol Cell Biol 1993 ; 13 : 7874-80.
- 34. Jacobs JJL, Kieboom K, Marino S, et al. The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the INK4a locus. Nature 1999 ; 397 : 164-8.
- 35. Itahana K, Zou Y, Itahana Y, et al. Control of the replicative life span of human fibroblasts by p16 and polycomb protein Bmi-1. Mol Cell Biol 2003 ; 23 : 389-401.
- 36. Dellino GI, Schwartz YB, Farkas G, et al. Polycomb silencing blocks transcription initiation. Mol Cell 2004 ; 13 : 887-93.
- 37. Costello JF, Berger MS, Huang HS, et al. Silencing of p16/CDKN2 expression in humain gliomas by methylation and chromatin condensation. Cancer Res 1996 ; 56 : 2405-10.
- 38. Fournel M, Sapieha P, Beaulieu N, et al. Down regulation of human DNA-(cytosine-5) methyltransferase induces cell cycle regulators p16INK4a and p21WAF/Cipl by distinct mechanisms. J Biol Chem 1999 ; 274 : 24250-6.
- 39. Robert MF, Morin S, Beaulieu N, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003 ; 33 : 61-5.
- 40. Bachman KE, Park BH, Rhee I, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer cell 2003 ; 3 : 89-95.
- 41. Magdinier F, Wolffe AP. Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc Natl Acad Sci USA 2001 ; 98 : 4990-5
- 42. Kondo E, Gu Z, Horii A, et al. The Thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16INK4a and hMLH1 genes. Mol Cell Biol 2005 ; 25 : 4388-96.
- 43. Ng HH, Zhang Y, Hendrich B, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 1999 ; 23 : 58-61.
- 44. Myöhänen S, Baylin SB. Sequence-specific DNA binding activity of RNA helicase A to the p16INK4a promoter. J Biol Chem 2001 ; 276 : 1634-42.
- 45. Oruetxebarria I, Venturini F, Kekarainen T, et al. p16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells. J Biol Chem 2004 ; 279 : 3807-16.
- 46. Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 2002 ; 298 : 1039-43.
- 47. Passegue E, Wagner EF. JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. EMBO J 2000 ; 19 : 2969-79.
- 48. Wang W, Wu J, Zhang Z, et al. Characterization of regulation elements on the promoter region of p16INK4a that contribute to overexpression of p16 in senescent fibroblasts. J Biol Chem 2001 ; 276 : 48655-61.
- 49. Jacobs JJ, Scheijen B, Voncken JW, et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999 ; 13 : 2678-90.