Identification and characterization of the protein-associated splicing factor as a negative co-regulator of the progesterone receptor
Identification and characterization of the protein-associated splicing factor as a negative co-regulator of the progesterone receptor
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DOI：
10.1074/jbc.m409187200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Lye, SJ
中科院分区：
文献类型：
--
作者：
Dong, XS;Shylnova, O;Lye, SJ
黄体酮在所有物种中对维持妊娠都是必不可少的，它的退出是激活子宫肌层和开始分娩所必需的。然而，与大多数其他物种不同的是，人类的黄体酮水平不会在足月时下降，这就提出了一个悖论，即在黄体酮的持续影响下，分娩是如何发生的。我们假设孕激素受体（PR）的内源性（子宫内膜）抑制因子可以诱导孕激素的功能性戒断，从而导致分娩的开始。我们以人PR为诱饵进行蛋白拉下实验，鉴定出聚嘧啶束结合蛋白相关剪接因子（PSF）为PR相互作用蛋白。在哺乳动物细胞中，PSF是一种有效的PR（而不是雌激素受体）转录活性抑制剂。它通过两种新的机制起作用，通过蛋白酶体途径诱导PR的降解，并干扰PR与其DNA反应元件的结合。重要的是，在大鼠体内的研究表明，子宫肌层PSF的表达在足月时急剧增加，这与子宫肌层PR水平的暂时降低有关。因此，我们提出PSF作为PR的辅助抑制因子，有助于黄体酮的功能性退出和人类分娩的开始。
Progesterone is essential in all species for the maintenance of pregnancy, and its withdrawal is required to activate the myometrium and to initiate labor. However, unlike most other species, progesterone levels do not fall at term in humans, raising the paradox as to how labor can occur under the continued influence of progesterone. We hypothesized that an endogenous (myometrial) repressor of the progesterone receptor (PR) could induce a functional withdrawal of progesterone and hence lead to the initiation of labor. We used the human PR as bait in a protein pull-down assay and identified polypyrimidine tract-binding protein-associated splicing factor (PSF) as a PR-interacting protein. PSF functions as a potent inhibitor of PR (but not estrogen receptor) transcriptional activity in mammalian cells. It acts through two novel mechanisms, inducing degradation of the PR through the proteasomal pathway and also interfering with binding of PR to its DNA response element. Importantly, in vivo studies in rats demonstrated a dramatic increase in myometrial PSF expression at term that was temporally associated with reduced levels of the myometrial PR. Accordingly, we propose that PSF acts as a PR corepressor and contributes to the functional withdrawal of progesterone and the initiation of human labor.