Activation of the human estrogen receptor by the antiestrogens ICI 182,780 and tamoxifen in yeast genetic systems: implications for their mechanism of action.
Activation of the human estrogen receptor by the antiestrogens ICI 182,780 and tamoxifen in yeast genetic systems: implications for their mechanism of action.
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DOI：
10.1073/pnas.97.7.3696
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发表时间：
2000-03
影响因子：
11.1
通讯作者：
Mark W. Dudley;Cameron Q. Sheeler;Hong Wang;Sohaib A. Khan
中科院分区：
文献类型：
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作者：
Mark W. Dudley;Cameron Q. Sheeler;Hong Wang;Sohaib A. Khan
抗雌激素他莫昔芬和ICI 182780被描述为人类雌激素受体(ER) α形式的雌激素结合位点的竞争性拮抗剂。然而，在功能研究中，这两种化合物都不能一直阻断雌二醇诱导的转录。在本报告中，研究人员利用三种酵母遗传系统研究了他莫昔芬和ICI 182780对ER二聚化、转录激活以及受体与共激活因子RIP140相互作用的影响。他莫昔芬和ICI 182,780能够诱导内质网二聚化和内质网依赖性转录，尽管其浓度比雌二醇高15,000倍。在RIP140存在的情况下，雌二醇和两种抗雌激素的转录应答最大值增加了30倍。整个酵母细胞[(3)H]雌二醇结合研究表明，他莫昔芬可以取代雌激素受体中的雌二醇，而ICI 182780处理导致[(3)H]雌二醇与受体结合增加4倍。他莫昔芬或ICI 182780在任何酵母模型中均未观察到雌二醇的拮抗作用。我们得出结论，他莫昔芬和ICI 182780等化合物的抗雌激素活性不是由它们竞争性地拮抗雌二醇与激素结合位点的能力引起的，而可能是由它们诱导er依赖性转录的能力引起的，这在哺乳动物系统中会导致受体下调。他莫昔芬等化合物通过激素结合位点起作用，而ICI 182780可能通过变构结合位点引起受体激活。
The antiestrogens tamoxifen and ICI 182,780 have been portrayed as competitive antagonists of the estrogen binding site of the alpha-form of the human estrogen receptor (ER). However, in functional studies, neither compound has consistently been able to block estradiol-induced transcription. In this report, three yeast genetic systems were used to investigate the effects of tamoxifen and ICI 182,780 on ER dimerization, transcriptional activation, and the interaction of the receptor with a coactivator, RIP140. Tamoxifen and ICI 182,780 were able to induce ER dimerization and ER-dependent transcription, albeit at up to 15,000-fold higher concentrations than that of estradiol. In the presence of RIP140, the transcription response maximum was increased up to 30-fold for estradiol and both antiestrogens. Whole yeast cell [(3)H]estradiol binding studies demonstrated that tamoxifen could displace the estradiol from the ER, whereas ICI 182,780 treatment resulted in a 4-fold increase in [(3)H]estradiol binding to the receptor. No antagonism of estradiol was observed with tamoxifen or ICI 182,780 in any of the yeast models employed. We have concluded that the antiestrogen activity of compounds like tamoxifen and ICI 182,780 is not caused by their ability to competitively antagonize estradiol binding to the hormone binding site, but possibly by their ability to induce ER-dependent transcription, which in mammalian systems would result in receptor down-regulation. Compounds such as tamoxifen act through the hormone binding site, whereas ICI 182,780 may cause receptor activation through an allosteric binding site.