The AF-1 Activation Function of Estrogen Receptor α Is Necessary and Sufficient for Uterine Epithelial Cell Proliferation In Vivo
The AF-1 Activation Function of Estrogen Receptor α Is Necessary and Sufficient for Uterine Epithelial Cell Proliferation In Vivo
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DOI：
10.1210/en.2012-2059
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发表时间：
2013-06-01
期刊：
影响因子：
4.8
通讯作者：
Arnal, Jean-Francois
中科院分区：
文献类型：
--
作者：
Abot, Anne;Fontaine, Coralie;Arnal, Jean-Francois
雌激素受体β（ERα）通过2个激活功能区（AFs）AF - 1和AF - 2调节基因转录。先前已证明ERα AF - 2在17β - 雌二醇（E2）对子宫内膜的增殖作用中起关键作用。在此，我们研究了ERα AF - 1在子宫中对基因转录和细胞增殖的调节作用。我们发现，用E2或他莫昔芬（可选择性激活ERα AF - 1）进行急性处理，对野生型小鼠子宫中一组雌激素依赖性基因的表达以及上皮细胞增殖有相似的调节作用。在缺乏ERα AF - 1（ERα AF - 1（0））的小鼠中，这些作用消失。4周的E2处理导致野生型小鼠子宫肥大以及腔上皮和基质细胞持续增殖，但在ERα AF - 1（0）小鼠中则没有。然而，ERα AF - 1（0）小鼠仍出现中度子宫肥大，主要是由于基质水肿，可能是由于血管内皮生长因子 - a（Vegf - a）诱导的持续存在。在这些ERα AF - 1（0）子宫中，上皮细胞凋亡大幅减少，对孕酮的反应也发生改变。最后，在一种ERα阳性的上皮癌细胞系中，E2诱导的增殖也因一种缺乏AF - 1的可诱导ERα异构体的过表达而受到抑制。总之，这些数据强调了ERα AF - 1在体外和体内E2诱导的增殖反应中的关键作用。由于先前报道ERα AF - 1对几种E2的生殖外保护作用是可有可无的，因此使用激活ERα且ERα AF - 1作用最小的分子可获得最佳的ERα调节。
Estrogen receptor-beta (ER alpha) regulates gene transcription through the 2 activation functions (AFs) AF-1 and AF-2. The crucial role of ER alpha AF-2 was previously demonstrated for endometrial proliferative action of 17 beta-estradiol (E2). Here, we investigated the role of ER alpha AF-1 in the regulation of gene transcription and cell proliferation in the uterus. We show that acute treatment with E2 or tamoxifen, which selectively activates ER alpha AF-1, similarly regulate the expression of a uterine set of estrogen-dependent genes as well as epithelial cell proliferation in the uterus of wild-type mice. These effects were abrogated in mice lacking ER alpha AF-1 (ER alpha AF-1(0)). Four weeks of E2 treatment led to uterine hypertrophy and sustained luminal epithelial and stromal cell proliferation in wild-type mice, but not in ER alpha AF-1(0) mice. However, ER alpha AF-1(0) mice still presented a moderate uterine hypertrophy essentially due to a stromal edema, potentially due to the persistence of Vegf-a induction. Epithelial apoptosis is largely decreased in these ER alpha AF-1(0) uteri, and response to progesteroneis also altered. Finally, E2-induced proliferation of an ER alpha-positive epithelial cancer cell line was also inhibited by overexpression of an inducible ER alpha isoform lacking AF-1. Altogether, these data highlight the crucial role of ER alpha AF-1 in the E2-induced proliferative response in vitro and in vivo. Because ER alpha AF-1 was previously reported to be dispensable for several E2 extrareproductive protective effects, an optimal ER alpha modulation could be obtained using molecules activating ER alpha with a minimal ER alpha AF-1 action.