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Altérations De La Voie De L'ampc Dans La Tumorigénèse Cortico-Surrénalienne: Étude Des Phosphodiestérases PDE11A Et PDE8B

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Altérations De La Voie De L'ampc Dans La Tumorigénèse Cortico-Surrénalienne: Étude Des Phosphodiestérases PDE11A Et PDE8B UNIVERSITE PARIS 5 RENE DESCARTES Ecole Doctorale Gc2iD THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE PARIS 5 RENE DESCARTES Discipline : Biologie Moléculaire et Cellulaire Présentée et soutenue publiquement par Delphine VEZZOSI Le 30 novembre 2012 Altérations de la voie de l'AMPc dans la tumorigénèse cortico-surrénalienne: étude des phosphodiestérases PDE11A et PDE8B Directeur de thèse : Monsieur le Professeur Jérôme Bertherat Jury Dr Grégoire VANDESCASTEELE Président Pr Olivier CHABRE Rapporteur Dr Pierre VAL Rapporteur Dr Estelle LOUISET Examinateur Pr Jérôme BERTHERAT Directeur de recherche 1 UNIVERSITE PARIS 5 RENE DESCARTES Ecole Doctorale Gc2iD THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE PARIS 5 RENE DESCARTES Discipline : Biologie Moléculaire et Cellulaire Présentée et soutenue publiquement par Delphine VEZZOSI Le 30 novembre 2012 Altérations de la voie de l'AMPc dans la tumorigénèse cortico-surrénalienne: étude des phosphodiestérases PDE11A et PDE8B Directeur de thèse : Monsieur le Professeur Jérôme Bertherat Jury Dr Grégoire VANDESCASTEELE Président Pr Olivier CHABRE Rapporteur Dr Pierre VAL Rapporteur Dr Estelle LOUISET Examinateur Pr Jérôme BERTHERAT Directeur de recherche 1 Remerciements Remerciements Je remercie tout d’abord M le Pr BERTHERAT pour m’avoir intégré au sein de votre équipe et pour m’avoir fait confiance pendant ces années de thèse. J’espère avoir été à la hauteur de vos espérances. Merci également pour toutes vos remontées de moral et vos réassurances dans les périodes de doutes « mais si c’est certain, tu vas réussir à la terminer cette thèse ». Merci… Je remercie également M le Dr Pierre VAL et M le Pr Olivier CHABRE pour avoir accepté la lourde charge d’être rapporteurs et pour avoir consacré de votre temps à lire le manuscrit. Vous avez contribué par vos remarques et vos suggestions à améliorer la qualité du mémoire, et je vous en suis très reconnaissante. Je tiens également à exprimer ma gratitude à M le Dr Grégoire VANDECASTEELE pour m’avoir accueilli dans ton laboratoire, m’avoir initié aux expériences de FRET, et avoir accepté de juger ce travail en tant que président du jury. J’associe à ces remerciements Mme le Dr Estelle LOUISET pour l’intérêt que vous avez porté à ce travail et pour avoir accepté de siéger à ce jury de thèse. Un travail de thèse ne se fait jamais en solitaire et je remercie donc de tout cœur tous les membres de l’Equipe 10 Tumeurs endocrines et signalisation de l’Institut Cochin, anciens et nouveaux, qui ont participé de près ou de loin à cette aventure : Marthe pour ton sourire, tes encouragements et pour m’avoir tenu la main lors des manips de l’activité PKA, Guillaume pour ton aide précieuse lors du travail sur le transcriptome, Bruno pour m’avoir initié à toutes les techniques de biologie moléculaire et aux secrets des muffins, Fernande pour avoir toujours accepté avec le sourire de m’aider pour les broyages de tumeurs, Rossella pour ton aide dans le travail sur PDE11, et tous les autres avec qui j’ai passé de très bons moments au labo, Karine, Léopoldine, Lionel, Pierre, Lucie, Amato, Olivia, Hortense, Stéphane, Laure, Sébastien, Marine, Camille, Stéphanie, Frédérique, Marie Laure… Je n’oublie pas mes petites cellules HEK 293 et H295R qui ont sacrifié leur vie pour que je puisse soutenir cette thèse. Cette thèse a été réalisée grâce au soutien financier de l’INCa que je remercie. Sans eux ce travail n’aurait pas été possible. Je tiens également à remercier toute l’équipe d’endocrinologie du CHU de Toulouse avec qui j’ai beaucoup de plaisir à travailler quotidiennement. Je n’oublie évidemment pas ceux qui me sont chers, ma maman pour son soutien indéfectible et mon papa qui, je l’espère, aurait été fier de moi, ainsi que le reste de ma famille, ma belle famille et mes amis. Enfin un merci tout spécial à mes deux amours : Grégoire pour tout ce que nous partageons et pour ton aide et ta patience lors des moments de rush lors de la préparation de cette thèse et Tom, parce que te voir grandir est un bonheur de tous 2 Remerciements les jours. Merci aussi Tom pour tes 100 000 « et pourquoi ? » quotidiens qui nous permettent ton papa et moi de nous remettre en question tous les jours. 3 Liste des abréviations Liste des abréviations ACTH: Adreno-corticotropic hormone AIMAH: ACTH-independent macronodular adrenal hyperplasia AIP: aryl hydrocarbone AKAP: A kinase anchoring protein AMPc: adenosine monophosphate cyclique ANP: atrial natriuretic peptide ATP: adenosine-5’-triphosphate BPCO: Bronchopneumopathie chronique obstructive GMPc: guanosine-3’-5’monophosphate GDP: Guanosine diphosphate GTP: Guanosine triphosphate HCG: Human Chorionic Gonadotropin IBMX: 3-isobutyl-1methylxanthine IGF1: Insulin-Like Growth Factor 1 GLP1: Glucagon-like peptide-1 LH: Luteinizing hormone MAP-kinase: Mitogen-activated protein kinase NO : Oxide nitrique PDE : Phosphodiesterase PPNAD : Primary Pigmented Nodular Adrenal Disease = dysplasie micronodulaire pigmentée bilatérale des surrénales PRKAR1A: Sous unité régulatrice R1A de la protéine kinase A RCPG : Récepteur couplé aux protéines G 4 Table des matières Table des matières REMERCIEMENTS .............................................................................................................................................. 2 LISTE DES ABREVIATIONS ............................................................................................................................. 4 TABLE DES MATIERES .................................................................................................................................... 5 TABLE DES ILLUSTRATIONS ......................................................................................................................... 7 1 FIGURES ..................................................................................................................................................... 7 2 TABLEAUX ................................................................................................................................................. 7 SYNTHESE BIBLIOGRAPHIQUE .................................................................................................................... 8 1 LA VOIE DE L’AMP CYCLIQUE (AMPC) .............................................................................................. 8 2 VOIE DE L’AMPC ET STEROÏDOGENESE ........................................................................................ 10 3 VOIE DE L’AMPC ET TUMEURS ENDOCRINES .............................................................................. 11 4 LES TUMEURS DE LA CORTICOSURRENALE ............................................................................... 16 4.1 LES LESIONS BENIGNES DE LA CORTICOSURRENALE ............................................................................. 17 4.1.1 L’adénome corticosurrénalien .................................................................................................. 17 4.1.2 L’hyperplasie corticosurrénalienne .......................................................................................... 19 4.1.3 Les lésions malignes de la corticosurrénale ........................................................................... 20 5 LES PHOSPHODIESTERASES ............................................................................................................ 20 5.1 STRUCTURE DES PDE S ......................................................................................................................... 22 5.1.1 Le domaine catalytique .............................................................................................................. 23 5.1.2 Le domaine N-terminal .............................................................................................................. 26 5.1.3 Le domaine C-terminal .............................................................................................................. 29 5.2 DIMERISATION DES PDE S ...................................................................................................................... 29 5.3 LOCALISATION TISSULAIRE DES PDE S ................................................................................................... 30 5.3.1 PDE1 ............................................................................................................................................ 30 5.3.2 PDE2 ............................................................................................................................................ 31 5.3.3 PDE3 ............................................................................................................................................ 31 5.3.4 PDE4 ............................................................................................................................................ 31 5.3.5 PDE5 ............................................................................................................................................ 32 5.3.6 PDE6 ............................................................................................................................................ 32 5.3.7 PDE7 ............................................................................................................................................ 32 5.3.8 PDE8 ............................................................................................................................................ 33 5.3.9 PDE9 ...........................................................................................................................................
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