Récepteurs des androgènes constitutivement actifs dans le cancer de la prostate,interconnexions avec les voies de signalisation
Langue Anglais
Ce document est protégé en vertu du Code de la Propriété Intellectuelle.
Auteur : Marcias, Gemma
Date de soutenance : 08-12-2009
Directeur(s) de thèse : Ceraline, Jocelyn - Culig, Zoran
Établissement de soutenance : Université de Strasbourg
École doctorale : École doctorale Sciences de la vie et de la santé (Strasbourg ; 2000-....)
Discipline : Aspects moléculaires et cellulaires de la biologie
Classification : Sciences de la vie, biologie, biochimie, Médecine et santé
Mots-clés libres : Prostate
Mots-clés :
- Prostate
- Thèses et écrits académiques
- Androgènes
- Thèses et écrits académiques
Résumé : The emergence of androgen receptor (AR) mutations is a key event in the progression of prostate cancer (PCa) toward androgen-independency. The AR protein consists in four functional domains: 1) the N-terminal region containing the activation function 1(AF-1) that is responsible for ligand-independent activity of the AR; 2) a central DNA binding domain (DBD) containing two zinc fingers; 3) the hinge region that encompasses a nuclear localization signal (NLS); 4) the C-terminal end (CTE) that includes the ligand binding domain (LBD) and AF-2. Mutations issued from clonal selection conferring new properties to the AR may be involved in PCa progression, bone metastasis and tumour growth under hormonal-treatment. The analysis of human tumour samples from localized and metastatic PCa allowed the identification of a new class of CTE-truncated mutant ARs. These mutant ARs the result of somatic nonsense mutations, and were twenty fold more frquent in hormone-refractory PCa that in hormone-naïve PCa. Furthermore, recent data proposed aberrant splicing as an alternative mechanism for CTE-truncated ARs. In the present study, we confirmed the coexistence of these two mechanisms, which offers a new preclinical model of hormoneresistant PCa. Investigations on the CTE-truncated Q640X AR have revealed in previous studies the constitutive nuclear localisation and the ligand-independent transcriptional activities of this CTE-truncated AR. Since the AR is a phosphoprotein, we explored the role of kinases signalling pathways in the activity of the Q640X AR. Our present results suggest that this AR mutant requires activating phosphorylation by PI3K/Akt and the MEK1-2 proteins, for full transactivation or transcriptional activities. Furthermore, we demonstrated that serine at position 213 in the AR sequence remains fundamental for signal transduction from PI3K/Akt kinases. In LNCaP cells, we have previously shown that the Q640X AR stimulates transcriptional activities of transcription factors such as NFAT and AP-1. We demonstrate that activation of Phospholipase C is a prerequisite for NFAT activity. In addition, we provide evidence that the crosstalk between truncated AR and NFAT or AP-1 factors depends on upstream signalling pathways. Altogether, our data indicate that Q640X AR requires activating phosphorylation by growth factors signalling pathways for full transcriptional activities. Moreover, this CTE-truncated AR may enhance some ligand/membrane receptors signalling to activate NFAT and AP-1. In conclusion, expression of CTE- truncated ARs may provide a mechanism for resistance to hormonal therapy. Understanding their functional properties ARs will allow the identification of new targeted therapies for the treatment of hormonal resistant PCa. Targeting the PI3K/Akt pathway may be a useful strategy for treating patients with hormone-refractory PCa positive for CTE truncated ARs.
Entrepôt d'origine : 
Identifiant : ecrin-ori-298809
Type de ressource : Thèse
