Résumés
Résumé
L’homologie de structure et d’organisation génique existant entre p53 et ses deux homologues, p73 et p63, suggère des fonctions biologiques similaires. Néanmoins des différences notables existent entre les membres de la famille p53. Ainsi, p53 est fréquemment muté dans les cancers humains, contrairement à p73 et p63. De plus, à l’opposé de p53 dont le transcrit majoritaire couvre tous les exons du gène, p73 et p63 codent pour deux types d’isoformes aux effets biologiques opposés: les unes, contenant un domaine de transactivation (TAD), ont des propriétés de protéine suppresseur de tumeur, tandis que les autres, dépourvues de TAD, possèdent des propriétés oncogéniques. Par ailleurs, si p53 répond aux stimulus génotoxiques, ses homologues participent au développement et à la différenciation tissulaires: tissu neuronal pour p73, tissu épithélial pour p63. Mais les trois membres de la famille p53 peuvent coopérer étroitement lors de la réponse cellulaire consécutive à un dommage génotoxique. Les tumeurs neuroblastiques, qui reproduisent les différents stades de différenciation des cellules du système nerveux sympathique, constituent un modèle de choix pour étudier les relations entre p53 et p73, ainsi que la régulation de leur expression.
Summary
Homologies in sequence and gene organization of p53 and their relatives, p73 and p63, suggest similar biological functions. However differences exist between the p53 family members. Indeed in human tumors p53 is often mutated while p63 and p73 are very rarely mutated. In addition, in contrast to p53 which is transcribed in a unique mRNA species spanning all gene exons, each homologue expresses two types of isoforms: some with transactivation domain (TAD) showing tumor suppressive properties, the others deprived of TAD, with oncogenic properties. If p53 responds to immediate genotoxic stress, its homologues participate to the cell homeostasis of specific tissues along their development and differentiation, neuronal tissue for p73, epithelial for p63. However a collaboration between the three p53 family members has been shown to occur in response to cell genotoxic damages. Neuroblastic tumors characterized by a large spectrum of neuronal differentiation constitute a good model to study relationship between p73 and p53 as well as the regulation of their respective expression.
Parties annexes
Références
- 1. Soussi T, May P. Structural aspects of the p53 protein in relation to gene evolution: second look. J Mol Biol 1996; 260: 623-37.
- 2. Courtois S, Verhaegh G, North S, et al. DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 2002; 44: 6722-8.
- 3. Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809-19.
- 4. Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating death-inducing and dominant negative activities. Mol Cell 1998; 2: 305-16.
- 5. Yang A, Kaghad M, Caput D, McKeon F. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 2002; 18: 90-5.
- 6. Nakagawa T, Takahashi M, Ozaki T, et al. Autoinhibitory regulation of p73 by ΔNp73 to modulate cell survival and death through a p73-specific target element within the ΔNp73 promoter. Mol Cell Biol 2002; 22: 2575-85.
- 7. Kartasheva N, Contente A, Lenz-Stöppler C, et al. p53 induces the expression p73 delta N, establishing an autoregulatory feedback loop. Oncogene 2002; 21: 4715-22.
- 8. Vossio S, Palescandolo E, Pediconi N, et al. DeltaN-p73 is activated after DNA damage in a p53-dependent manner to regulate p53-induced cell cycle arrest. Oncogene 2002; 21: 3796-803.
- 9. Larsen CJ. The ARF-p53 pathway: a line of defense against oncogenic signals. Bull Cancer 1998; 85: 9-19.
- 10. Zeng X, Chen L, Jost CA, et al. Mdm2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol 1999; 19: 3257-66.
- 11. Minty A, Dumont X, Kaghad M, Caput D. Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1 interacting proteins and a SUMO-1 interaction motif. J Biol Chem 2000; 275: 36316-23.
- 12. Calabro V, Gelsomina M, Parisi T, et al. The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63. J Biol Chem 2002; 277: 2674-81.
- 13. Stiewe T, Pützer BM. Role of p73 in malignancy tumor suppressor or oncogene? Cell Death Differ 2002; 9: 237-45.
- 14. Jost CA, Marin MC, Kaelin WG. p73 is a human p53-related protein that can induce apoptosis. Nature 1997; 389: 191-4.
- 15. Flores ER, Tsai KY, Crowley D, et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 2002; 416: 560-4.
- 16. Sah VP, Attardi LD, Mulligan GJ, et al. A subset of p53-deficient embryos exhibit exencephaly. Nat Genet 1995; 10: 175-80.
- 17. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356: 215-21.
- 18. Miller FD, Pozniak CD, Walsh GS. Neuronal life and death: an essential role for the p53 family. Cell Death Differ 2000; 7: 800-88.
- 19. Lowe S, Ryley H, Jacks T, Houssman D. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74: 957-67.
- 20. Mills AA, Zheng B, Wang XJ, et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398: 708-13.
- 21. Celli J, Duijf P, Hamel BC, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 1999; 99: 143-53.
- 22. Yang A, Walker N, Bronson R, et al. p73-deficient mice have neurobiological, pheromonal and inflammatory defects but lack spontaneous tumors. Nature 2000; 404: 99-103.
- 23. Pozniak CD, Radinovic S, Yang A, et al. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science 2000; 289: 304-6.
- 24. Meyer G, Perez-Garcia CG, Abraham H, Caput D. Expression of p73 and Reelin in the developing human cortex. J Neurosci 2002; 22: 4973-86.
- 25. Allart S, Martin H, Détraves C, et al. Human cytomegalovirus induces drug resistance and alteration of programmed cell death by accumulation of ΔN-p73. J Biol Chem 2002; 277: 29063-8.
- 26. Moll UT, LaQuaglia M, Bénard J, Riou G. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci USA 1995; 92: 4407-11.
- 27. Wolff A, Technau A, Ihling C, et al. Evidence that wild-type p53 in neuroblastoma cells is in a conformation refractory to integration into the transcriptional complex. Oncogene 2001; 20: 1307-17.
- 28. Naka M, Ozaki T, Takada N, et al. Functional characterization of naturally occurring mutants (P405R and P425L) or p73alpha and p73beta found in neuroblastoma and lung cancer. Oncogene 2001; 14: 3568-72.
- 29. Ahomadegbe JC, Tourpin S, Kaghad M, et al. Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancer: prevalence of alterations in inflammatory breast cancers. Oncogene 2000; 19: 5413-8.
- 30. Yan H, Yuan W, Velculescu VE, et al. Allelic variation of human gene expression. Science 2002; 297: 1143.
- 31. Fillippovich I, Sorokina N, Gatei M, et al. Transactivation deficient p73alpha (p73 Deltaexon2) inhibits apoptosis and competes with p53. Oncogene 2001; 2: 514-22.
- 32. Douc-Rasy S, Barrois M, Echeynne M, et al. DeltaN-p73alpha accumulates in human neuroblastic tumors. Am J Pathol 2002; 160: 631-9.
- 33. Zaika A, Slade N, Erster S, et al. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med 2002; 196: 765-80.
- 34. Casciano I, Mazzocco K, Boni L, et al. Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ 2002; 9: 229-30.
- 35. De Laurenzi V, Raschella G, Barcaroli D, et al. Induction of neuronal differentiation by p73 in a neuroblastoma cell line. J Biol Chem 2000; 27: 15226-31.
- 36. Nikolaev AY, Li M, Puskas N, et al. Parc: a cytoplasmic anchor for p53. Cell 2003; 112: 29-40.
- 37. Goldschneider D, Blanc E, Raguenez G, et al. Forced p73 expression induces nuclear accumulation of endogenous p53 protein. Cancer Lett 2003; 197: 99-103.
- 38. Goldschneider D, Blanc E, Raguenez G, et al. Differential response of p53 target to p73 overexpression in SH-SYSY neuroblastoma cell line. J. Cell Sci 2004; 117: 293-301.