p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4
p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4
复制标题
DOI：
10.1210/en.2008-0851
复制
发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
--
作者：
Inagaki, Kenichi;Otsuka, Fumio;Makino, Hirofumi
采用大鼠颗粒细胞与卵母细胞共培养的方法，研究了p38-MAPK通路在类固醇合成中的作用。激活素和卵泡刺激素容易使颗粒细胞中的p38磷酸化。激活素对p38磷酸化的影响可被选择性激活素受体样激酶-4、-5和-7抑制剂SB431542所消除。SB431542可抑制FSH诱导的雌二醇的合成，但对孕酮的生成无影响，cAMP也有一定程度的降低，提示内源性激活素主要参与雌二醇的合成。FSH诱导的p38激活不受SB431542和卵泡抑素的影响，提示FSH不是通过内源性激活素激活p38的。骨形态发生蛋白(BMP)-2和BMP-4也可促进FSH诱导的p38磷酸化，这种作用可通过卵母细胞的作用而增强。特异性p38抑制剂SB203580可减少FSH诱导的雌二醇的产生。然而，SB203580不能改变FSH诱导的cAMP积聚，这表明p38的激活与雌二醇的合成无关。BMP-2和BMP-4抑制FSH和Forsklin(FSK)诱导的孕酮和cAMP的合成，与卵母细胞的作用无关。BMP-2、BMP-4和激活素增加了FSH诱导的雌二醇的产生，在有卵母细胞存在的情况下，这种作用增强。与激活素增强FSK诱导的雌二醇相反，BMP-2和BMP-4对FSK诱导的雌二醇的产生没有影响，提示BMP-2和BMP-4直接激活FSH受体信号。由于激活素增加，而BMP-2和BMP-4减少，FSH诱导的cAMP，BMP-2和BMP-4对雌二醇的促进作用似乎与cAMP-蛋白激酶A途径不同。因此，BMP-2和BMP-4通过刺激FSH诱导的p38和抑制cAMP来不同地调节类固醇的生成。前者参与雌二醇的产生，并通过卵母细胞的作用增强，而后者则导致孕酮合成减少。(内分泌学150：1921-1930,2009)
Roles of the p38-MAPK pathway in steroidogenesis were investigated using coculture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective activin receptor-like kinase-4, -5, and -7 inhibitor, SB431542. SB431542 decreased FSH-induced estradiol but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. Bone morphogenetic protein (BMP)-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin (FSK)-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4, and activin increased FSH- induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced FSK-induced estradiol, BMP-2 and BMP-4 had no effects on FSK-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH- receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH- induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from the cAMP-protein kinase A pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH- induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, whereas the latter leads to reduction of progesterone synthesis. (Endocrinology 150: 1921-1930, 2009)