A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition
A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition
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DOI：
10.1073/pnas.1633616100
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发表时间：
2003-08-05
影响因子：
11.1
通讯作者：
Mendelson, CR
中科院分区：
文献类型：
--
作者：
Condon, JC;Jeyasuria, P;Mendelson, CR
导致人类和其他哺乳动物分娩的分子事件尚不清楚。我们认为，子宫肌层中含有组蛋白乙酰化酶活性的辅激活因子的下降可能通过损害孕酮-孕酮受体（PR）复合物的功能而导致分娩的发生。通过半定量和实时RT-PCR、免疫组化和免疫印迹评估，PR辅激活因子cAMP反应元件结合蛋白（CREB）结合蛋白和类固醇受体辅激活因子2和3的表达在分娩妇女的子宫底组织中降低。使用小鼠作为动物模型，我们还发现在足月子宫组织中共激活因子水平降低。在人类和小鼠中，足月子宫组织中乙酰化组蛋白H3的水平也降低。在妊娠后期给予孕鼠一种特异性和有效的组蛋白去乙酰化酶抑制剂-这些结果表明，PR辅激活因子表达和组蛋白乙酰化的下降，在子宫近期可能会损害PR功能，引起功能性孕酮撤退。由此导致的PR反应基因表达的减少应增加子宫对收缩刺激的敏感性。
The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone-progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24-48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.