Fiche publication
Date publication
août 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Billon-Gales A, Krust A, Fontaine C, Abot A, Flouriot G, Toutain C, Berges H, Gadeau AP, Lenfant F, Gourdy P, Chambon P, Arnal JF
Lien Pubmed
Résumé
17beta-Estradiol (E2) regulates estrogen receptor-alpha (ERalpha) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding domain of ERalpha, respectively. We previously reported that ERalpha is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERalphaAF2 in these two major beneficial actions of E2 by electively targeting ERalphaAF2 (named ERalphaAF2(0)). Our results prove four points. (i) Compared with WT ERalpha, the ability of ERalphaAF2(0) to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERalpha. (ii) The uterotrophic action of E2 was totally absent in ERalphaAF2(0) mice, showing the crucial role of ERalphaAF2 in E2-induced uterus hyperplasia. (iii) ERalphaAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERalphaAF2(0) in vivo. (iv) Finally, the atheroprotective effect of E2 was abrogated in ERalphaAF2(0) LDL-r(-/-) mice. Thus, whereas ERalphaAF1 and ERalphaAF2 are both required for the uterotrophic action of E2, we show that only ERalphaAF2 is necessary for its atheroprotective effect.
Référence
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13311-6
