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Etude De 2 Gènes Cibles De La Protéine P53 : Siah (Seven in Absentia Human Homologue) Et Tsap6 (Tumor Suppressor Activated Pathway 6) Séverine Beaucourt

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Etude De 2 Gènes Cibles De La Protéine P53 : Siah (Seven in Absentia Human Homologue) Et Tsap6 (Tumor Suppressor Activated Pathway 6) Séverine Beaucourt Etude de 2 gènes cibles de la protéine P53 : siah (seven in absentia human homologue) et tsap6 (tumor suppressor activated pathway 6) Séverine Beaucourt To cite this version: Séverine Beaucourt. Etude de 2 gènes cibles de la protéine P53 : siah (seven in absentia human homologue) et tsap6 (tumor suppressor activated pathway 6). Biologie cellulaire. Université Paris Sud - Paris XI, 2005. Français. tel-00157749 HAL Id: tel-00157749 https://tel.archives-ouvertes.fr/tel-00157749 Submitted on 27 Jun 2007 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. "I am satisfied with the mystery of life's eternity and with the awareness of--and glimpse into--the marvelous construction of the existing world together with the steadfast determination to comprehend a portion, be it ever so tiny, of the reason that manifests itself in nature. This is the basis of cosmic religiosity, and it appears to me that the most important function of art and science is to awaken this feeling among the receptive and keep it alive." Albert Einstein Avant-propos Je souhaiterais avant toute chose remercier Adam Telerman et Robert Amson pour m'avoir fait confiance tout au long de ces années, et surtout à mon arrivée au laboratoire lorsque je cherchais un stage qui devait marquer la "fin de mes études". C'est grâce à leurs encouragements et à ceux de toute l'équipe que j'ai entrepris de faire cette thèse. Merci de m'avoir permis de travailler sur ce fascinant projet qu'est la réversion tumorale. Je voudrais remercier Bruno Goud et Pierre Hainaut pour m'avoir fait l'honneur d'être les rapporteurs de ce manuscrit. Merci également aux autres membres du jury, François Dautry et Jean Cavarelli, d'avoir accepté de participer à ma soutenance. Ce travail n'aurait pas été possible sans la coopération et le soutien de tout le laboratoire. Merci tout d'abord à Giusy qui a dirigé la majorité des travaux que j'ai réalisé durant ces 4 années de doctorat. Merci également à Marcel aux côtés duquel j'ai pu travailler à mes débuts chez MEL. Merci à Alexandra, Dominique, Anne, Pamela et Nathalie qui ont toutes contribué activement aux résultats présentés ici ; mais surtout avec qui j'ai pu travailler au quotidien dans la bonne humeur, la confiance et le respect. Merci à Vanessa et Christophe pour leur soutien, leurs nombreux conseils techniques et stratégiques tant au cours de la réalisation que de la rédaction de ces expériences. Merci à Virginie pour ses encouragements constants. Merci à Sylvie pour m'avoir accordé sa confiance dès le jour où j'ai passé la porte du laboratoire et pour m'avoir appris beaucoup lors de mes premiers mois chez MEL. Je n'oublie pas de remercier Laurent et Stéphanie ainsi que les personnes qui ont auparavant travaillé sur ce projet de réversion tumorale qui nous tient tous tant à cœur. Je tiens également à remercier les personnes qui ont contribué à l'avancée de ces travaux ; en particulier Moshe Oren et Bohdan Wasylyk pour leurs conseils, leur confiance et leur aide technique. Mes remerciements vont également à Pierre Chambon et son équipe, Michel Vidal, Shu-Ren Wang, Valérie Goutty et Astrid Rey pour leur aide concernant les souris. Je voudrais aussi adresser mes remerciements à Johannes Grosse et ses collègues de la société Ingenium pour nous avoir fourni les souris TSAP6 mutantes. Je n'oublie pas que c'est grâce à certains de mes professeurs que j'ai acquis des méthodes de travail, et que j'ai découvert et aimé la science et surtout la biologie. Je voudrais aussi remercier les amis qui m'ont apporté leur soutien, leur amitié et leur joie de vivre. Ils se reconnaitront. Un grand merci à mes parents, mes grands parents, à Stéfanie et à Rémi pour m'avoir entouré, conseillé et encouragé depuis toujours. Enfin et surtout, MERCI à Méryl pour tant de choses, et en particulier pour avoir concédé que je le fasse parfois passer après mon travail durant ces quatre ans. Etude de 2 gènes cibles de la protéine P53 : siah et tsap6 Table des matières Table des matières ____________________________________________________ 1 Table des illustrations__________________________________________________ 4 Table des annexes_____________________________________________________ 5 Résumé _____________________________________________________________ 6 Abréviations _________________________________________________________ 7 Nomenclature ________________________________________________________ 7 Introduction _________________________________________________________ 8 I - Suppression et réversion tumorale ____________________________________ 11 I.1 - Bref historique sur la suppression tumorale __________________________________ 11 I.2 - La réversion tumorale____________________________________________________ 13 II - P53 ____________________________________________________________ 18 II.1 - La découverte de P53____________________________________________________ 18 II.2 - p53 : oncogène ou gène suppresseur de tumeur ? _____________________________ 18 II.2.1 - p53 serait un oncogène ?_____________________________________________ 18 II.2.2 - p53 : un gène suppresseur de tumeur ___________________________________ 19 II.3 - P53 et le cycle cellulaire__________________________________________________ 19 II.4 - P53 et le cancer_________________________________________________________ 20 II.5 - P53 est un facteur de transcription_________________________________________ 21 II.5.1 - La découverte de l'activité de facteur de transcription ______________________ 21 II.5.2 - Le site consensus de liaison de P53 sur l'ADN ____________________________ 21 II.5.3 - Un facteur de transcription sous forme tétramérique _______________________ 21 II.5.4 - Les gènes de réponse à P53___________________________________________ 22 II.5.4.1 - Généralités __________________________________________________________ 22 II.5.4.2 - Le gène p21/waf1/cip1 _________________________________________________ 23 II.5.4.3 - Les gènes tsip et tsap___________________________________________________ 23 II.6 - Les activités de P53 indépendantes de la transcription ________________________ 24 II.6.1 - La régulation de l'activité d'autres protéines ______________________________ 24 II.6.2 - La réparation de l'ADN______________________________________________ 24 II.6.3 - Les autres fonctions de P53 __________________________________________ 24 II.7 - La régulation de P53 ____________________________________________________ 25 II.7.1 - La régulation au niveau transcriptionnel_________________________________ 25 II.7.2 - La régulation au niveau traductionnel___________________________________ 25 II.7.3 - La régulation au niveau post-traductionnel_______________________________ 25 II.7.3.1 - La phosphorylation de P53 ______________________________________________ 26 II.7.3.2 - L'acétylation de P53 ___________________________________________________ 26 II.7.3.3 - La méthylation de P53__________________________________________________ 26 II.7.3.4 - L'ubiquitination de P53 _________________________________________________ 26 II.7.3.4.1 - La poly-ubiquitination et la dégradation de P53 par le protéasome______________________ 26 II.7.3.4.2 - La mono-ubiquitination de P53_________________________________________________ 27 II.7.3.5 - Les autres modifications de P53 __________________________________________ 27 II.7.4 - La régulation par la boucle Mdm2 : une balance subtile ____________________ 27 II.7.5 - La régulation de la fonction de P53 ____________________________________ 28 II.7.5.1 - Les conditions de l'activation de P53 ______________________________________ 28 II.7.5.2 - La balance apoptose/arrêt de croissance ____________________________________ 29 II.8 - Une activité anti-apoptotique paradoxale de P53 _____________________________ 30 II.9 - Les dernières découvertes liées à P53_______________________________________ 30 III - Introduction aux gènes siah ________________________________________ 33 III.1 - Une famille de gènes fortement conservés __________________________________ 33 III.1.1 - Le membre fondateur : le gène sina de drosophile ________________________ 33 III.1.2 - Les homologues chez les mammifères__________________________________ 34 III.1.2.1 - Les gènes siah-1______________________________________________________ 34 III.1.2.1.1 - Siah-1 chez la souris ________________________________________________________ 34 III.1.2.1.2 - Siah-1 chez l'humain ________________________________________________________ 35 1 Etude de 2 gènes cibles de la protéine P53 : siah et tsap6 III.1.2.2 - Le gène siah-2 _______________________________________________________ 35 III.2 - Structure des protéines de la famille Siah __________________________________ 37 III.2.1 - Structure générale _________________________________________________ 37 III.2.2 - Un domaine RING_________________________________________________ 37 III.2.3 - Un domaine de liaison au substrat _____________________________________ 37 III.2.4 - Un domaine d'oligomérisation ________________________________________ 38 III.2.5 - Un domaine de localisation nucléaire __________________________________
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