Scarpin Katherine M, Graham J Dinny, Mote Patricia A, Clarke Christine L
Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney Western Clinical School, Westmead, NSW, Australia.
Nucl Recept Signal. 2009 Dec 31;7:e009. doi: 10.1621/nrs.07009.
Progesterone is a critical regulator of normal female reproductive function, with diverse tissue-specific effects in the human. The effects of progesterone are mediated by its nuclear receptor (PR) that is expressed as two isoforms, PRA and PRB, which are virtually identical except that PRA lacks 164 amino acids that are present at the N-terminus of PRB. Considerable in vitro evidence suggests that the two PRs are functionally distinct and in animals, tissue-specific distribution patterns of PRA and PRB may account for some of the diversity of progesterone effects. In the human, PRA and PRB are equivalently expressed in most target cells, suggesting that alternative mechanisms control the diversity of progesterone actions. PR mediates the effects of progesterone by association with a range of coregulatory proteins and binding to specific target sequences in progesterone-regulated gene promoters. Ligand activation of PR results in redistribution into discrete subnuclear foci that are detectable by immunofluorescence, probably representing aggregates of multiple transcriptionally active PR-coregulator complexes. PR foci are aberrant in cancers, suggesting that the coregulator composition and number of complexes is altered. A large family of coregulators is now described and the range of proteins known to bind PR exceeds the complement required for transcriptional activation, suggesting that in the human, tissue-specific coregulator expression may modulate progesterone response. In this review, we examine the role of nuclear localization of PR, coregulator association and tissue-specific expression in modulating progesterone action in the human.
孕酮是正常女性生殖功能的关键调节因子，在人体内具有多种组织特异性作用。孕酮的作用由其核受体（PR）介导，该受体以两种亚型PRA和PRB的形式表达，除了PRA缺少PRB N端存在的164个氨基酸外，它们几乎完全相同。大量体外证据表明，这两种PR在功能上是不同的，在动物中，PRA和PRB的组织特异性分布模式可能解释了孕酮作用的一些多样性。在人类中，PRA和PRB在大多数靶细胞中表达相当，这表明存在其他机制控制孕酮作用的多样性。PR通过与一系列共调节蛋白结合并与孕酮调节基因启动子中的特定靶序列结合来介导孕酮的作用。PR的配体激活导致重新分布到可通过免疫荧光检测到的离散核内亚结构域中，这可能代表多个转录活性PR-共调节蛋白复合物的聚集体。PR亚结构域在癌症中是异常的，这表明共调节蛋白的组成和复合物的数量发生了改变。现在已经描述了一大类共调节蛋白，已知与PR结合的蛋白质范围超过了转录激活所需的补充，这表明在人类中，组织特异性共调节蛋白的表达可能调节孕酮反应。在这篇综述中，我们研究了PR的核定位、共调节蛋白结合和组织特异性表达在调节人类孕酮作用中的作用。
