雌性生殖组织中孕酮受体活性的动态调控。

S J Han, F J DeMayo, B W O'Malley
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引用次数: 9

摘要

孕激素受体(PR)与协同调节复合物合作协调女性生殖的关键过程。为了研究PR活性在体内的动态调控,利用PR活性指示剂(PRAI)系统构建了一种新的转基因小鼠模型。利用PRAI小鼠的研究表明,黄体酮可以暂时调节雌性生殖组织中的PR活性。具体来说,黄体酮在给药后立即迅速增强PR活动。然而,慢性黄体酮刺激会抑制女性生殖器官的PR活性。与黄体酮一样,RU486也能暂时调节女性生殖器官中的PR活性。然而,RU486对PR活性的时间调节与黄体酮的活性相反。在雌性生殖组织中,RU486注射后急性抑制PR活性,慢性治疗后PR活性升高。与天然激素相比,使用PR的混合拮抗剂/激动剂治疗会导致细胞内PR活性、共调节因子水平和激酶活性的组织特异性模式显著不同。PR与类固醇受体共激活因子(src)的协调相互作用促进了基因表达的转录调控。双基因prap - src敲除小鼠模型使我们能够绘制组织特异性PR活性的共激活因子图谱。基于这一图谱,我们得出结论,PR在不同组织中的内源性生理功能受到不同src的调节。SRC-3是乳腺PR的主要共激活因子,SRC-1是子宫PR的主要共激活因子。
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Dynamic regulation of progesterone receptor activity in female reproductive tissues.

The progesterone receptor (PR) in cooperation with coregulator complexes coordinates crucial processes in female reproduction. To investigate the dynamic regulation of PR activity in vivo, a new transgenic mouse model utilizing a PR activity indicator (PRAI) system was generated. Studies utilizing the PRAI mouse have revealed that progesterone temporally regulates PR activity in female reproductive tissues. Specifically, progesterone rapidly enhances PR activity immediately after administration. However, chronic progesterone stimulation represses PR activity in female reproductive organs. Like progesterone, RU486 also temporally regulates PR activity in female reproductive organs. However, the temporal regulation of PR activity by RU486 is the inverse of progesterone's activity. RU486 acutely represses PR activity after injection but increases PR activity after chronic treatment in female reproductive tissues. Treatment with a mixed antagonist/agonist of PR, when compared to natural hormone, results in dramatically different tissue-specific patterns of intracellular PR activity, coregulator levels, and kinase activity. Transcriptional regulation of gene expression by PR is facilitated by coordinate interactions with the steroid receptor coactivators (SRCs). Bigenic PRAI-SRC knockout mouse models enabled us to draw a tissue-specific coactivator atlas for PR activity in vivo. Based on this atlas, we conclude that the endogenous physiological function of PR in distinct tissues is modulated by different SRCs. SRC-3 is the primary coactivator for PR in the breast and SRC-1 is the primary coactivator for PR in the uterus.

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