Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors.
Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors.
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类固醇激素受体之间的抑制性串扰：雌激素受体通过激动剂和拮抗剂占据的孕激素受体抑制其转录活性的差异靶向。
DOI：
10.1128/mcb.15.4.1847
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发表时间：
1995
影响因子：
5.3
通讯作者：
Katzenellenbogen,BS
中科院分区：
文献类型：
--
作者：
Kraus,WL;Weis,KE;Katzenellenbogen,BS
虽然雌激素受体（ER）和孕激素受体（PR）是不同类固醇激素受体亚家族的成员，但有相当多的生物学证据表明雌激素和孕激素受体信号通路之间存在串扰。我们开发了一个模型系统来分析这种串扰的机制，特别是PR与拮抗或激动配体络合对er介导的转录活性的抑制。将含有多种启动子的雌激素和孕激素应答性报告载体转染到大鼠子宫细胞和3T3小鼠成纤维细胞的原代培养物中，并表达PR （a和/或B亚型）和ER。我们的研究结果表明，这两种PR亚型都可以作为内质网活性的有效配体依赖性抑制因子。抑制的程度取决于PR亚型（即PR A或PR B）、配体类型（即激动剂或拮抗剂）、PR水平和配体浓度，但不受ER水平的影响。启动子上下文在确定激动剂占据的PR的抑制幅度和PR异构体特异性方面是重要的，而拮抗剂占据的PR则不是。配体占据的PR A比配体占据的PR B更能抑制er介导的转录活性。拮抗剂占据的PR是比激动剂占据的PR更有效的抑制因子。机制研究表明，配体PR通过干扰其与转录机制有效相互作用的能力来抑制内质网活性，这一过程被称为猝灭。数据不支持竞争性抑制、直接抑制或压制作为PR抑制作用的机制。内质网突变体的实验表明，受体激动剂占据的PR抑制内质网的n端部分是必需的，而拮抗剂占据的PR则不需要。这些结果以及两种PR配体复合物之间的其他差异表明，它们在抑制内质网转录活性时靶向内质网是不同的。这些发现强调了类固醇激素受体家族成员之间相互作用的重要性。
Although estrogen receptor (ER) and progestin receptor (PR) are members of different steroid hormone receptor subfamilies, there is considerable biological evidence for cross-talk between the estrogen and pro-gestin hormone-receptor signaling pathways. We have developed a model system to analyze the mechanisms underlying this cross-talk, specifically the repression of ER-mediated transcriptional activity by PR complexed with agonistic or antagonistic ligands. Estrogen- and progestin-responsive reporter vectors containing a variety of promoters were transfected into primary cultures of rat uterine cells and 3T3 mouse fibroblasts with expression vectors for PR (the A and/or B isoforms) as well as ER. Our results demonstrate that both PR isoforms can act as potent ligand-dependent repressors of ER activity. The magnitude of the repression was dependent on the PR isoform (i.e., PR A or PR B), ligand type (i.e., agonist or antagonist), PR levels, and ligand concentration but was unaffected by the ER levels. The promoter context was important in determining both the magnitude and PR isoform specificity of the repression for agonist-occupied PR but not for antagonist-occupied PR. Ligand-occupied PR A was a stronger repressor of ER-mediated transcriptional activity than was ligand-occupied PR B, and antagonist-occupied PR was a more effective repressor than agonist-occupied PR. Mechanistic studies suggest that liganded PR represses ER activity by interfering with its ability to interact productively with the transcriptional machinery, a process known as quenching. The data do not support competitive repression, direct repression, or squelching as the mechanism of PR's inhibitory effect. Experiments with ER mutants demonstrated that the N-terminal portion of ER was required for repression by agonist-occupied PR but not by antagonist-occupied PR. These results, as well as other differences between the two PR-ligand complexes, suggest that they differentially target ER when repressing ER transcriptional activity. These findings underscore the mounting evidence for the importance of interactions between members of the steroid hormone receptor family.