The CCAAT/enhancer binding protein beta is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization.
The CCAAT/enhancer binding protein beta is a critical regulator of steroid-induced mitotic expansion of uterine stromal cells during decidualization.
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DOI：
10.1210/en.2009-1437
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发表时间：
2010-08
期刊：
影响因子：
4.8
通讯作者：
Wei Wang;Quanxi Li;I. Bagchi;M. Bagchi
中科院分区：
文献类型：
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作者：
Wei Wang;Quanxi Li;I. Bagchi;M. Bagchi
在怀孕早期，母体类固醇激素、雌激素和孕激素的协同作用促进了一个独特的过程，称为蜕膜化，该过程涉及子宫基质细胞的广泛增殖和分化。胚胎植入的必要先决条件，这种胚胎诱导的细胞转化的分子途径仍然知之甚少。我们以前确定CCAAT/增强子结合蛋白β（C/EBP β）作为子宫类固醇调节的靶点。缺乏C/EBP β的小鼠的子宫不能进行蜕膜化。在本研究中，对C/EBP β缺失子宫的分析表明，该因子的缺失导致基质细胞对蜕膜刺激的增殖反应受阻。突变体基质细胞进入细胞周期S期，完成DNA合成，但不能进行有丝分裂。进一步的分析显示，C/EBP β通过直接结合细胞周期蛋白B2启动子来调节其表达，从而促进这些细胞向有丝分裂的转变。cdc 25 C的表达，一种磷酸酶，在有丝分裂期间维持细胞周期蛋白B-细胞周期蛋白依赖性激酶复合物的活性状态，在C/EBP β-null基质细胞中也受到强烈抑制。此外，在有丝分裂期之前，肿瘤抑制因子p53和细胞周期抑制因子p21和p27的表达在C/EBP β缺失的基质细胞中显著升高，揭示了C/EBP β控制G2向M过渡的其他机制。总的来说，这些结果表明，C/EBP β介导的作用，类固醇激素在蜕膜化过程中，通过调节多个关键的细胞周期调控因子的表达，控制增殖子宫基质细胞的G2到M的过渡。
During early pregnancy, the concerted actions of the maternal steroid hormones, estrogen and progesterone, promote a unique process known as decidualization, which involves extensive proliferation and differentiation of uterine stromal cells. The molecular pathways underlying this hormonally induced cellular transformation, an essential prerequisite for embryo implantation, remain poorly understood. We previously identified CCAAT/enhancer binding protein beta (C/EBPbeta) as a target of steroid regulation in the uterus. Uteri of mice lacking C/EBPbeta failed to undergo decidualization. In the present study, analyses of C/EBPbeta-null uteri indicated that loss of this factor leads to a block in stromal cell proliferation in response to a decidual stimulation. The mutant stromal cells entered S phase of the cell cycle and completed DNA synthesis but were unable to execute mitosis. Further analysis revealed that C/EBPbeta facilitates the transition of these cells into mitosis by binding directly to the cyclin B2 promoter to regulate its expression. The expression of cdc25C, a phosphatase that maintains the active state of the cyclin B-cyclin-dependent kinase complex during mitosis, is also strongly suppressed in C/EBPbeta-null stromal cells. Furthermore, the expression of the tumor suppressor p53 and the cell cycle inhibitors p21 and p27 was markedly elevated in C/EBPbeta-null stromal cells before the mitotic phase, uncovering additional mechanisms by which C/EBPbeta controls G2 to M transition. Collectively, these results revealed that C/EBPbeta mediates the effects of steroid hormones during decidualization by modulating the expression of multiple key cell cycle regulatory factors that control the G2 to M transition of the proliferating uterine stromal cells.