Requirement for ERK1/2 activation in the regulation of progesterone production in human granulosa-lutein cells is stimulus specific
Requirement for ERK1/2 activation in the regulation of progesterone production in human granulosa-lutein cells is stimulus specific
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DOI：
10.1210/en.143.3.877
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发表时间：
2002-03-01
期刊：
影响因子：
4.8
通讯作者：
Wheeler-Jones, CPD
中科院分区：
文献类型：
--
作者：
Dewi, DA;Abayasekara, DRE;Wheeler-Jones, CPD
本研究旨在确定 MAPK 的 ERK1/2 家族是否可以通过人黄体的生理调节因子进行调节，以及这种激活是否对人颗粒黄体素 (hGL) 细胞中的孕酮分泌很重要。人 LH (hLH)、hCG 和间接升高 cAMP [霍乱毒素、毛喉素、(Bu)(2)CAMP] 的药物，在 hGL 细胞中以时间和剂量依赖性方式激活 ERK1/2。与 PKA 抑制剂（包括肉豆蔻酰化 PKI）预孵育可减少 ERK1/2 激活，表明 cAMP 介导 ERK1/2 激活。两种结构不同的 MAPK 激酶 (MEK) 抑制剂 PD 98059 和 U 0126 可消除 hLH/hCG 诱导的 ERK1/2 激活，但对 hLH、hCG 或 22R-羟基胆固醇刺激的孕酮分泌没有影响。相比之下，两种抑制剂均可阻断霍乱毒素、毛喉素和 (Bu)(2)cAMP 诱导的 ERK1/2 磷酸化，同时伴随孕激素分泌减少。已知的促黄体素 PGE(2) 可促进 ERK1/2 的 MEK 和 cAMP 依赖性激活，MEK 或 PKA 抑制剂可减少 PGE(2) 诱导的孕酮合成。我们的研究结果表明，hGL 细胞中 ERK1/2 激活作为黄体酮合成调节剂的需要是刺激依赖性的，并且 MEK 抑制剂敏感步骤是远端的。与 cAMP 的生成有关，但最接近于胆固醇向孕烯醇酮的转化。
This study was conducted to determine whether the ERK1/2 family of MAPKs can be modulated by physiological regulators of the human corpus luteum, and whether this activation is important for progesterone secretion in human granulosalutein (hGL) cells. Human LH (hLH), hCG, and agents that indirectly elevate cAMP [cholera toxin, forskolin, (Bu)(2)CAMP], time- and dose-dependently activated ERK1/2 in hGL cells. ERK1/2 activation was reduced by preincubation with PKA inhibitors, including myristoylated PKI, suggesting that cAMP mediates ERK1/2 activation. Two structurally distinct inhibitors of MAPK kinase (MEK), PD 98059 and U 0126, abrogated hLH/hCG-induced ERK1/2 activation, but had no effect on hLH-, hCG-, or 22R-hydroxycholesterol-stimulated progesterone secretion. In contrast, both inhibitors blocked cholera toxin-, forskolin-, and (Bu)(2)cAMP-induced ERK1/2 phosphorylation concomitant with a reduction in progesterone secretion. The known luteotropin, PGE(2), promoted MEK- and cAMP-dependent activation of ERK1/2, and inhibitors of either MEK or PKA decreased PGE(2)-induced progesterone synthesis. Our findings demonstrate that the requirement for ERK1/2 activation as a regulator of progesterone synthesis in hGL cells is stimulus dependent, and that the MEK inhibitor-sensitive step is distal. to cAMP generation, but proximal to the conversion of cholesterol to pregnenolone.