Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1.
Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1.
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DOI：
10.1210/mend.12.7.0138
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发表时间：
1998-07
影响因子：
--
通讯作者：
R. Robker;J. Richards
中科院分区：
文献类型：
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作者：
R. Robker;J. Richards
颗粒细胞的增殖和终末分化对正常的卵泡生长、排卵和黄体生成至关重要。因此，我们分析了细胞周期激活因子（cyclin D1， D2和D3）和细胞周期抑制剂（p27Kip1和p21Cip1）在卵泡生长和分化的特定阶段小鼠和大鼠卵巢中的原位定位和激素调节。细胞周期蛋白D2 mRNA特异性定位于生长卵泡颗粒细胞，而细胞周期蛋白D1和细胞周期蛋白D3仅限于卵泡细胞。在去垂体(H)大鼠中，雌二醇或卵泡刺激素处理后颗粒细胞中细胞周期蛋白D2 mRNA和蛋白水平均升高，两种激素处理后细胞周期蛋白D2 mRNA和蛋白水平均升高。在无血清培养的大鼠颗粒细胞中，FSH、forskolin和雌二醇使cyclin D2 mRNA迅速升高，表明雌二醇和cAMP可以直接和独立地增加cyclin D2的表达。p27Kip1蛋白水平在雌二醇或卵泡刺激素的作用下没有升高。相比之下，当将排卵剂量的人CG （LH）给予激素启动的H大鼠以刺激黄体生成化时，细胞周期蛋白D2 mRNA和蛋白在4小时内迅速下降且无法检测到，特别是在大卵泡的颗粒细胞中。同样，在LH作用下，细胞周期抑制剂p27Kip1在12 - 24小时内被诱导表达（p21Cip1在4小时内被诱导），并在黄体组织中特异性升高。cyclin D2-/-小鼠的卵泡在激素依赖阶段的卵泡生长中起着关键作用，卵泡在激素的作用下不会快速生长，但表达FSH/LH作用、细胞周期退出和终末分化的标记物。综上所述，这些数据表明FSH和雌二醇通过增加周期蛋白D2（相对于p27Kip1）的水平来调节排卵前卵泡发育过程中的颗粒细胞增殖，而LH通过下调周期蛋白D2同时上调p27Kip1和p21Cip1来终止卵泡生长。
The proliferation and terminal differentiation of granulosa cells are critical for normal follicular growth, ovulation, and luteinization. Therefore, the in situ localization and hormonal regulation of cell cycle activators (cyclin D1, D2, and D3) and cell cycle inhibitors (p27Kip1 and p21Cip1) were analyzed in ovaries of mice and rats at defined stages of follicular growth and differentiation. Cyclin D2 mRNA was specifically localized to granulosa cells of growing follicles, while cyclin D1 and cyclin D3 were restricted to theca cells. In hypophysectomized (H) rats, cyclin D2 mRNA and protein were increased in granulosa cells by treatment with estradiol or FSH and were increased maximally by treatment with both hormones. In serum-free cultures of rat granulosa cells, cyclin D2 mRNA was rapidly elevated in response to FSH, forskolin, and estradiol, indicating that estradiol as well as cAMP can act directly and independently to increase cyclin D2 expression. The levels of p27Kip1 protein were not increased in response to estradiol or FSH. In contrast, when ovulatory doses of human CG (LH) were administered to hormonally primed H rats to stimulate luteinization, cyclin D2 mRNA and protein were rapidly decreased and undetectable within 4 h, specifically in granulosa cells of large follicles. Also in response to LH, the expression of the cell cycle inhibitor p27Kip1 was induced between 12 and 24 h (p21Cip1 was induced within 4 h) and remained elevated specifically in luteal tissue. A critical role for cyclin D2 in the hormone-dependent phase of follicular growth is illustrated by the ovarian follicles of cyclin D2-/- mice, which do not undergo rapid growth in response to hormones, but do express markers of FSH/LH action, cell cycle exit, and terminal differentiation. Collectively, these data indicate that FSH and estradiol regulate granulosa cell proliferation during the development of preovulatory follicles by increasing levels of cyclin D2 relative to p27Kip1 and that LH terminates follicular growth by down-regulating cyclin D2 concurrent with up-regulation of p27Kip1 and p21Cip1.