TY - JOUR
T1 - The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity
AU - Fontaine, Coralie
AU - Buscato, Melissa
AU - Vinel, Alexia
AU - Giton, Frank
AU - Raymond-Letron, Isabelle
AU - Kim, Sung Hoon
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
AU - Gourdy, Pierre
AU - Milon, Alain
AU - Flouriot, Gilles
AU - Ohlsson, Claes
AU - Lenfant, Françoise
AU - Arnal, Jean François
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/4/5
Y1 - 2020/4/5
N2 - 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.
AB - 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.
KW - Activation function (AF)
KW - Dose response
KW - Estrogen receptor alpha (ERα)
KW - Tissue-specificity
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U2 - 10.1016/j.mce.2020.110741
DO - 10.1016/j.mce.2020.110741
M3 - Article
C2 - 32004676
AN - SCOPUS:85078714369
SN - 0303-7207
VL - 505
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
M1 - 110741
ER -