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首页> 外文期刊>Molecular and Cellular Biology >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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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.

机译：类固醇激素受体之间的抑制性串扰：激动剂和拮抗剂占据的孕激素受体抑制雌激素受体转录活性的差异性靶向。

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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 progestin 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.
机译：尽管雌激素受体（ER）和孕激素受体（PR）是不同类固醇激素受体亚家族的成员，但是有大量生物学证据证明雌激素和孕激素受体信号通路之间存在相互干扰。我们已经开发了一个模型系统来分析这种串扰的机制，特别是通过与激动或拮抗配体复合的PR抑制ER介导的转录活性。将含有多种启动子的雌激素和孕激素反应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，并带有PR（A和/或B同种型）和ER表达载体。我们的结果表明，两种PR同工型均可以作为有效的配体依赖性ER活性阻遏物。抑制的程度取决于PR同工型（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。启动子的背景对于确定激动剂占据的PR而不是拮抗剂占据的PR的阻抑幅度和PR同工型特异性都很重要。与配体占据的PR B相比，配体占据的PR A是ER介导的转录活性的更强阻遏物，而与激动剂占据的PR相比，配体占据的PR A是更有效的阻遏物。机理研究表明，配体PR通过干扰ER与转录机制有效相互作用的能力来抑制ER活性，这一过程称为淬灭。数据不支持竞争性抑制，直接抑制或抑制作为PR抑制作用的机制。用ER突变体进行的实验表明，激动剂占据的PR而不是拮抗剂占据的PR抑制ER的N端部分是必需的。这些结果，以及两个PR-配体复合物之间的其他差异，表明它们在抑制ER转录活性时有差异地靶向ER。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。

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