Katzenellenbogen B S
Department of Molecular and Integrative Physiology, Physiology, University of 61801-3704, USA.
Biol Reprod. 1996 Feb;54(2):287-93. doi: 10.1095/biolreprod54.2.287.
Estrogens regulate the growth, differentiation, and functioning of diverse target tissues, both within and outside of the reproductive system. Most of the actions of estrogens appear to be exerted via the estrogen receptor (ER) of target cells, an intracellular receptor that is a member of a large superfamily of proteins that function as ligand-activated transcription factors, regulating the synthesis of specific RNAs and proteins. To understand how the ER discriminates between estrogen ligands, which activate the ER, and antiestrogen ligands, which fail to effectively activate the ER, we have generated and analyzed human estrogen receptors with mutations in the ER hormone binding domain. These studies provide evidence for the promoter-specific and cell-specific actions of the estrogen-occupied and antiestrogen-occupied and antiestrogen-occupied ER, highlight a regional dissociation of the hormone binding and transcription activation functions in domain E of the receptor, and indicate that some of the contact sites of estrogens and antiestrogens in the ER are likely different. In addition, multiple interactions among different cellular signaling pathways are involved in the regulation of gene expression and cell proliferation by the ER. In several cell types, protein kinase activators and some growth factors enhance the transcriptional activity of the ER. Cyclic AMP also alters the agonist/antagonist balance of some antiestrogens. Estrogens and, to a lesser extent, antiestrogens, as well as protein kinase activators and growth factors increase phosphorylation of the ER and possibly other proteins involved in the ER-specific response pathway, suggesting that changes in cellular phosphorylation state will be important in determining the biological activity of the ER and the effectiveness of antiestrogens as estrogen antagonists. The ER also has important interrelationships with the progesterone receptor (PR) system in modulation of biological responses. Liganded PR-A and PR-B can each suppress estradiol-stimulated ER activity, with the magnitude of repression dependent on the PR isoform, progestin ligand, promoter, and cell type. These findings underscore the mounting evidence for the importance of interactions between members of the steroid hormone receptor family.
雌激素调节生殖系统内外多种靶组织的生长、分化和功能。雌激素的大多数作用似乎是通过靶细胞的雌激素受体（ER）发挥的，ER是一种细胞内受体，属于一个大型蛋白质超家族的成员，该超家族的蛋白质作为配体激活的转录因子发挥作用，调节特定RNA和蛋白质的合成。为了了解ER如何区分激活ER的雌激素配体和不能有效激活ER的抗雌激素配体，我们生成并分析了在ER激素结合域有突变的人雌激素受体。这些研究为雌激素占据、抗雌激素占据和抗雌激素占据的ER的启动子特异性和细胞特异性作用提供了证据，突出了受体E结构域中激素结合和转录激活功能的区域解离，并表明雌激素和抗雌激素在ER中的一些接触位点可能不同。此外，不同细胞信号通路之间的多种相互作用参与了ER对基因表达和细胞增殖的调节。在几种细胞类型中，蛋白激酶激活剂和一些生长因子可增强ER的转录活性。环磷酸腺苷也会改变一些抗雌激素的激动剂/拮抗剂平衡。雌激素以及程度较轻的抗雌激素，以及蛋白激酶激活剂和生长因子会增加ER以及可能参与ER特异性反应途径的其他蛋白质的磷酸化，这表明细胞磷酸化状态的变化对于确定ER的生物学活性和抗雌激素作为雌激素拮抗剂的有效性将很重要。ER在调节生物学反应方面与孕酮受体（PR）系统也有重要的相互关系。配体结合的PR-A和PR-B均可抑制雌二醇刺激的ER活性，抑制程度取决于PR异构体、孕激素配体、启动子和细胞类型。这些发现强调了越来越多的证据表明类固醇激素受体家族成员之间相互作用的重要性。
