Mechanism of estrogen action:: Lessons from the estrogen receptor-α knockout mouse
Mechanism of estrogen action:: Lessons from the estrogen receptor-α knockout mouse
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DOI：
10.1095/biolreprod59.3.470
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发表时间：
1998-09-01
影响因子：
3.6
通讯作者：
Cunha, GR
中科院分区：
文献类型：
--
作者：
Cooke, PS;Buchanan, DL;Cunha, GR
E2在体内刺激子宫和阴道上皮细胞增殖[1]。E2在子宫和阴道生长和成人功能的其他方面也起着关键作用，并且对于这些器官中的正常上皮形态发生、细胞分化和分泌活性是必需的。E2通过雌激素受体（ER）发挥其作用，雌激素受体作为配体激活的转录因子在E2应答组织中打开靶基因。多年来，人们认为E2通过单一类型的ER起作用。然而，最近发现的第二种受体，命名为ERβ，以区别于现在称为ERα的原始受体，表明E2作用的介导比最初认为的更复杂。与ERα一样，ERβ是类固醇受体超家族的成员，在啮齿动物子宫和阴道中检测到低水平但可检测的ERβ mRNA和蛋白[3-5]。然而，ERα敲除（ERKO）小鼠的E2处理不会产生特征性雌激素反应，如阴道上皮分层和角化、子宫上皮DNA合成或子宫湿重和子宫孕酮受体、葡萄糖6-磷酸脱氢酶或乳铁蛋白的mRNA水平增加[6]，尽管这些动物的子宫和阴道中表达ERβ mRNA [4]。因此，尽管ERβ在女性生殖道中的作用尚未确定，但ERα似乎是介导通常与E2治疗相关的阴道和子宫反应的关键受体。因此，本综述将仅讨论ERα在各种E2诱导的过程（如上皮细胞增殖和分化）中的作用，而不会进一步讨论ERβ。ER在成人子宫和阴道的上皮细胞和基质细胞中表达[7，8]，最初假设E2对上皮和基质的作用直接通过这些组织隔室中的ER介导。近年来出现了一些与E2作用的这种看似明显的机制不一致的发现，并建议：
Estradiol-17β (E2) stimulates uterine and vaginal epithelial proliferation in vivo [1]. E2 also plays a critical role in other aspects of uterine and vaginal growth and adult function, and it is obligatory for normal epithelial morphogenesis, cytodifferentiation, and secretory activity in these organs. E2 elicits its effects via the estrogen receptor (ER), which functions as a ligand-activated transcription factor to turn on target genes in E2-responsive tissues. For many years it was believed that E2 acted through a single type of ER. However, the recent discovery [2, 3] of a second receptor, named ERβ to distinguish it from the original receptor now termed ERα, has indicated that mediation of E2 action is more complicated than originally thought. ERβ, like ERα, is a member of the steroid receptor superfamily, and low but detectable levels of ERβ mRNA and protein have been detected in the rodent uterus and vagina [3–5]. However, E2 treatment of ERα knockout (ERKO) mice does not produce characteristic estrogenic responses such as vaginal epithelial stratification and cornification, uterine epithelial DNA synthesis, or increases in uterine wet weight and mRNA levels for uterine progesterone receptor, glucose 6-phosphate dehydrogenase, or lactoferrin [6], despite the expression of ERβ mRNA in the uterus and vagina of these animals [4]. Therefore, although the role of ERβ in the female reproductive tract has not been established, ERα seems to be the critical receptor for mediating vaginal and uterine responses commonly associated with E2 treatment. This review will therefore address only the role of ERα in various E2-induced processes such as epithelial proliferation and differentiation and will not deal with ERβ further.ER is expressed in both epithelial and stromal cells of adult uterus and vagina [7, 8], and it was initially assumed that E2 effects on epithelium and stroma were mediated directly through ER in these tissue compartments. Several findings not consistent with this seemingly obvious mechanism of E2 action have appeared in recent years and sug-