Molecular mechanisms of estrogen action: selective ligands and receptor pharmacology
Molecular mechanisms of estrogen action: selective ligands and receptor pharmacology
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DOI：
10.1016/s0960-0760(00)00104-7
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发表时间：
2000-11-30
影响因子：
4.1
通讯作者：
Katzenellenbogen, JA
中科院分区：
文献类型：
--
作者：
Katzenellenbogen, BS;Choi, IH;Katzenellenbogen, JA
雌激素对多种靶细胞的生理产生深远的影响，这些影响似乎是由两种雌激素受体（ER）亚型，ER α和ER β介导的。我们研究了内质网配体，从纯激动剂到拮抗剂，如何与内质网α和内质网β相互作用，并调节它们在不同基因上的转录活性。突变定位-结构活性研究表明，内质网配体结合域的不同残基参与了结构上不同的雌激素和抗雌激素的识别。我们已经从不同结构的配体中发现，一些特别有趣的配体是通过内质网的高效选择性激动剂还有一些是通过内质网的完全激动剂同时是通过内质网的完全拮抗剂。抗雌激素药物，如羟他莫昔芬，是通过内质网α混合激动剂/拮抗剂，是通过内质网β在含有雌激素反应元件的基因位点进行纯拮抗剂。对ER α / β嵌合蛋白的研究表明，他莫昔芬的激动作用需要ER α的激活功能1区。通过双杂交实验，我们分离出了一种内质网特异性的共调节因子，它可以增强抗雌激素拮抗剂的有效性并抑制内质网的转录活性。我们也专注于了解抗雌激素和雌激素调节基因的不同药理学。虽然抗雌激素被认为主要是通过拮抗雌激素来起作用，但我们发现在一些新的内质网调节基因中，醌还原酶（QR），一种解毒的第11期抗氧化酶，其活性在乳腺癌细胞中以内质网依赖的方式被抗雌激素上调。这种反应被雌激素拮抗，因此显示出“反向药理学”。抗雌激素增加QR活性需要功能性内质网（ER α或ER β），有趣的是，它是通过QR基因5'调控区的亲电反应元件介导的。QR的上调可能有助于他莫昔芬、雷洛昔芬等抗雌激素药物在乳腺癌防治中的有益作用。雌激素迅速上调与细胞结构变化相关的几种基因的表达，包括NHE-RF，钠氢交换调节因子，也称为EBP50。NHE-RF/EBP50富集于微绒毛中，可能作为支架接头蛋白调控雌激素诱导的细胞结构和信号转导事件的早期变化。分析这些主要反应基因的调控区域，以及所涉及的抗氧化和其他信号通路，为了解作为选择性雌激素受体调节剂（SERMs）的配体对靶细胞的活性和特性发挥显著作用的机制提供了相当大的见解。因此，雌激素在其不同靶细胞中的有趣生物学特性是由配体的结构、所涉及的内质网亚型、激素反应基因启动子的性质以及调节细胞对内质网配体复合物反应的共激活因子和共抑制因子的特征和平衡决定的。作为雌激素受体α或雌激素受体β的选择性雌激素或抗雌激素的配体的持续发展，应该允许优化这些药物的组织选择性，用于更年期激素替代疗法和乳腺癌的治疗和预防。(C) 2000 Elsevier Science Ltd.版权所有。
Estrogens exert profound effects on the physiology of diverse target cells and these effects appear to be mediated by two estrogen receptor (ER) subtypes, ER alpha and ER beta. We have investigated how ER ligands, ranging from pure agonists to antagonists, interact with ER alpha and ER beta, and regulate their transcriptional activity on different genes. Mutational mapping-structure activity studies indicate that different residues of the ER ligand binding domain are involved in the recognition of structurally distinct estrogens and antiestrogens. We have identified from ligands of diverse structure, several particularly interesting ones that are high potency selective agonists via ER alpha and others that are full agonists through ER alpha while being full antagonists through ER beta. Antiestrogens such as hydroxytamoxifen, which are mixed agonist/antagonists through ER alpha are pure antagonists through ER beta at estrogen response element-containing gene sites. Studies with ER alpha/beta chimeric proteins reveal that tamoxifen agonism requires the activation function 1 region of ER alpha. Through two-hybrid assays, we have isolated an ER-specific coregulator that potentiates antiestrogen antagonist effectiveness and represses ER transcriptional activity. We have also focused on understanding the distinct pharmacologies of antiestrogen- and estrogen-regulated genes. Although antiestrogens are thought to largely act by antagonizing the actions of estrogens, we have found among several new ER-regulated genes, quinone reductase (QR), a detoxifying phase 11 antioxidant enzyme, that has its activity up-regulated by antiestrogens in an ER-dependent manner in breast cancer cells. This response is antagonized by estrogens, thus showing 'reversed pharmacology'. Increased QR activity by antiestrogens requires a functional ER (ER alpha or ER beta) and is, interestingly, mediated via the electrophile response element in the QR gene 5' regulatory region. The up-regulation of QR may contribute to the beneficial effects of tamoxifen, raloxifene, and other antiestrogens in breast cancer prevention and treatment. Estrogens rapidly up-regulate expression of several genes associated with cell cytoarchitectural changes including NHE-RF, the sodium hydrogen exchanger regulatory factor, also known as EBP50. NHE-RF/EBP50 is enriched in microvilli, and may serve as a scaffold adaptor protein in regulating early changes in cell architecture and signal transduction events induced by estrogen. Analyses of the regulatory regions of these primary response genes, and the antioxidant and other signaling pathways involved, are providing considerable insight into the mechanisms by which ligands, that function as selective estrogen receptor modulators or SERMs, exert their marked effects on the activities and properties of target cells. The intriguing biology of estrogens in its diverse target cells is thus determined by the structure of the ligand, the ER subtype involved, the nature of the hormone-responsive gene promoter, and the character and balance of coactivators and corepressors that modulate the cellular response to the ER-ligand complex. The continuing development of ligands that function as selective estrogens or antiestrogens for ER alpha or ER beta should allow optimized tissue selectivity of these agents for menopausal hormone replacement therapy and the treatment and prevention of breast cancer. (C) 2000 Elsevier Science Ltd. All rights reserved.