The CCAAT/Enhancer Binding Protein β Is a Critical Regulator of Steroid-Induced Mitotic Expansion of Uterine Stromal Cells during Decidualization

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/EBP beta) as a target of steroid regulation in the uterus. Uteri of mice lacking C/EBP beta failed to undergo decidualization. In the present study, analyses of C/EBP beta-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/EBP beta 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/EBP beta-null stromal cells. Furthermore, the expression of the tumor suppressor p53 and the cell cycle inhibitors p21 and p27 was markedly elevated in C/EBP beta-null stromal cells before the mitotic phase, uncovering additional mechanisms by which C/EBP beta controls G2 to M transition. Collectively, these results revealed that C/EBP beta 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. (Endocrinology 151: 3929-3940, 2010)