The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity

Coralie Fontaine (1) , Melissa Buscato (1) , Alexia Vinel (1) , Frank Giton (2) , Isabelle Raymond-Letron (3) , Sung Hoon Kim (4) , Benita S Katzenellenbogen (4) , John A Katzenellenbogen (4) , Pierre Gourdy (1) , Alain Milon (5) , Gilles Flouriot (6) , Claes Ohlsson (7) , Françoise Lenfant (1) , Jean-François Arnal (1)

1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 IMRB - Institut Mondor de Recherche Biomédicale
3 ENVT - Ecole Nationale Vétérinaire de Toulouse
4 UIUC - University of Illinois at Urbana-Champaign [Urbana]
5 IPBS - Institut de pharmacologie et de biologie structurale
6 Irset - Institut de recherche en santé, environnement et travail
7 EHESP - École des Hautes Études en Santé Publique [EHESP]

17β-Estradiol (E2) action can be mediated by the full-length estrogen receptor alpha (ERα66), and also by the AF1 domain-deficient ERα (ERα46) isoform, but their respective sensitivity to E2 is essentially unknown. We first performed a dose response study using subcutaneous home-made pellets mimicking either metestrus, proestrus or a pharmacological doses of E2, which resulted in plasma concentrations around 3, 30 and 600 pM, respectively. Analysis of the uterus, vagina and bone after chronic exposure to E2 demonstrated dose-dependent effects, with a maximal response reached at the proestrus-dose in wild type mice expressing mainly ERα66. In contrast, in transgenic mice harbouring only an ERα deleted in AF1, these effects of E2 were either strongly shifted rightward (10-100-fold) and/or attenuated, depending on the tissue studied. Finally, experiments in different cell lines transfected with ERα66 or ERα46 also delineated varying profiles of ERα AF1 sensitivity to E2. Altogether, this work emphasizes the importance of dose in the tissue-specific actions of E2 and demonstrates the key sensitizing role of AF1 in ERα activity.

Mots clés: Tissue-specific; Activation function (AF); Dose response; Estrogen receptor alpha (ERα)

Domaines: Endocrinologie et métabolisme

Coralie Fontaine, Melissa Buscato, Alexia Vinel, Frank Giton, Isabelle Raymond-Letron, et al.. The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity. Molecular and Cellular Endocrinology, 2020, 505, pp.110741. ⟨10.1016/j.mce.2020.110741⟩. ⟨hal-02470890⟩