Katzenellenbogen B S, Montano M M, Le Goff P, Schodin D J, Kraus W L, Bhardwaj B, Fujimoto N
Department of Physiology and Biophysics, University of Illinois, Urbana 61801, USA.
J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):387-93. doi: 10.1016/0960-0760(95)00084-d.
Antiestrogens, acting via the estrogen receptor (ER) evoke conformational changes in the ER and inhibit the effects of estrogens as well as exerting anti-growth factor activities. Although the binding of estrogens and antiestrogens is mutually competitive, studies with ER mutants indicate that some of the contact sites of estrogens and antiestrogens are likely different. Some mutations in the hormone-binding domain of the ER and deletions of C-terminal regions result in ligand discrimination mutants, i.e. receptors that are differentially altered in their ability to bind and/or mediate the actions of estrogens vs antiestrogens. Studies in a variety of cell lines and with different promoters indicate marked cell context- and promoter-dependence in the actions of antiestrogens and variant ERs. In several cell systems, estrogens and protein kinase activators such as cAMP synergize to enhance the transcriptional activity of the ER in a promoter-specific manner. In addition, cAMP changes the agonist/antagonist balance of tamoxifen-like antiestrogens, increasing their agonistic activity and reducing their efficacy in reversing estrogen actions. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors increase phosphorylation of the ER and/or proteins involved in the ER-specific response pathway. These changes in phosphorylation alter the biological effectiveness of the ER. Multiple interactions among different cellular signal transduction systems are involved in the regulation of cell proliferation and gene expression by estrogens and antiestrogens.
抗雌激素药物通过雌激素受体（ER）发挥作用，引起ER构象变化，抑制雌激素的作用，并发挥抗生长因子活性。尽管雌激素和抗雌激素的结合是相互竞争的，但对ER突变体的研究表明，雌激素和抗雌激素的一些接触位点可能不同。ER激素结合域的一些突变和C末端区域的缺失导致配体识别突变体，即那些在结合和/或介导雌激素与抗雌激素作用的能力上有差异改变的受体。在多种细胞系和不同启动子的研究表明，抗雌激素和变异ER的作用存在明显的细胞背景和启动子依赖性。在几个细胞系统中，雌激素和蛋白激酶激活剂如cAMP协同作用，以启动子特异性方式增强ER的转录活性。此外，cAMP改变了他莫昔芬样抗雌激素的激动剂/拮抗剂平衡，增加了它们的激动活性，并降低了它们逆转雌激素作用的效力。雌激素以及程度较轻的抗雌激素，还有蛋白激酶激活剂和生长因子，都会增加ER和/或参与ER特异性反应途径的蛋白质的磷酸化。这些磷酸化变化改变了ER的生物学效能。不同细胞信号转导系统之间的多种相互作用参与了雌激素和抗雌激素对细胞增殖和基因表达的调节。
