INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, Toulouse, France.
INSERM IMRB U955 Eq07, Créteil, France; AP-HP, Pôle Biologie-Pathologie Henri Mondor, Créteil, France.
Mol Cell Endocrinol. 2020 Apr 5;505:110741. doi: 10.1016/j.mce.2020.110741. Epub 2020 Jan 28.
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.
17β-雌二醇（E2）的作用可以通过全长雌激素受体α（ERα66）和缺乏 AF1 结构域的 ERα（ERα46）同工型介导，但它们对 E2 的敏感性基本未知。我们首先使用模拟发情期、发情前期或药理学剂量 E2 的皮下自制丸剂进行剂量反应研究，结果导致血浆浓度分别约为 3、30 和 600 pM。慢性暴露于 E2 后对子宫、阴道和骨骼的分析表明，在主要表达 ERα66 的野生型小鼠中，剂量依赖性反应达到最大反应在发情前期剂量。相比之下，在仅携带 AF1 缺失的 ERα 的转基因小鼠中，E2 的这些作用要么向右强烈移位（10-100 倍），要么减弱，这取决于所研究的组织。最后，用 ERα66 或 ERα46 转染的不同细胞系中的实验也描绘了 ERα AF1 对 E2 的敏感性的不同特征。总之，这项工作强调了剂量在 E2 的组织特异性作用中的重要性，并证明了 AF1 在 ERα 活性中的关键致敏作用。
