Division of Endocrinology, Department of Medicine, Beth Israel Medical Center and Albert Einstein College of Medicine, New York 10003, USA.
Horm Metab Res. 2011 Jun;43(6):386-90. doi: 10.1055/s-0031-1273760. Epub 2011 Mar 29.
Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis.
胰岛素和胰岛素样生长因子-I（IGF-I）参与卵巢甾体激素生成的调节。在胰岛素抵抗状态下，卵巢仍然对胰岛素敏感，因为胰岛素可以激活替代信号通路，如磷脂酰肌醇-3-激酶（PI-3 激酶）和丝裂原活化蛋白激酶（MAPK）通路，以及胰岛素受体和 1 型 IGF 受体。我们研究了 MAPK-Erk1/2 和 MAPK-p38 在胰岛素和 IGF-I 信号通路对人卵巢细胞孕激素生成中的作用。人卵巢细胞在组织培养基中培养，存在不同浓度的胰岛素或 IGF-I，有或没有 PD98059，一种特定的 MAPK-Erk1/2 抑制剂，有或没有 SB203580，一种特定的 MAPK-p38 抑制剂，或有或没有特定的 PI-3 激酶抑制剂 LY294002。使用放射免疫测定法测量孕激素浓度。PD98059 单独以剂量依赖的方式刺激孕激素生成，最高可达 65%（p<0.001）。同样，LY294002 单独刺激孕激素生成 13-18%（p<0.005）。然而，当一起使用时，PD98059 和 LY294002 抑制孕激素生成 17-20%（p<0.001）。SB203580 单独抑制孕激素生成 20-30%（p<0.001）。胰岛素或 IGF-I 单独刺激孕激素生成 40-60%（p<0.001）。在胰岛素研究中，PD98059 对孕激素合成没有显著影响，而 SB203580 消除了胰岛素诱导的孕激素生成。PD98059 或 SB203580 消除了 IGF-I 诱导的孕激素生成。MAPK-Erk1/2 和 MAPK-p38 都参与 IGF-I 诱导的孕激素生成信号通路，而胰岛素诱导的孕激素生成需要 MAPK-p38，但不需要 MAPK-Erk1/2。这些研究为胰岛素和 IGF-I 信号通路在人卵巢细胞甾体生成中的分歧提供了进一步的证据。
