Prostaglandin F2α Represses IGF-I-Stimulated IRS1/Phosphatidylinositol-3-Kinase/AKT Signaling in the Corpus Luteum: Role of ERK and P70 Ribosomal S6 Kinase
Prostaglandin F2α Represses IGF-I-Stimulated IRS1/Phosphatidylinositol-3-Kinase/AKT Signaling in the Corpus Luteum: Role of ERK and P70 Ribosomal S6 Kinase
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DOI：
10.1210/me.2009-0312
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发表时间：
2010-03-01
影响因子：
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通讯作者：
Davis, John S.
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文献类型：
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作者：
Arvisais, Edward;Hou, Xiaoying;Davis, John S.
对导致黄体退化的早期细胞内事件知之甚少。本实验旨在探讨前列腺素F2α(PGF2α)对黄体内磷脂酰肌醇-3-激酶(PI3K)/Akt信号转导的影响。用溶黄体剂量的PGF2α处理黄体中期奶牛后，ERK和哺乳动物靶标雷帕霉素(MTOR)/p70核糖体蛋白S6激酶(P70S6K1)信号迅速增加，黄体组织Akt磷酸化迅速抑制。在体外用PGF2α处理原代培养的黄体细胞也导致ERK和mTOR/p70S6K1信号的增加，IGF-I刺激PI3K、Akt和蛋白激酶C Zeta激活的能力减弱。由于PGF2α处理后PI3K和Akt活性降低，我们发现在体内和体外，PGF2α促进了胰岛素受体底物1(IRS1)肽序列中丝氨酸残基(307,612,636)的磷酸化。IRS1的丝氨酸磷酸化与IGF-I刺激的IRS1/PI3Kp85复合体的形成减少有关。此外，用MAPK/ERK或mTOR/p70S6K1信号通路的抑制剂处理可阻止PGF2α诱导的IRS1丝氨酸磷酸化，并取消PGF2α对Akt激活的抑制作用。综上所述，这些实验提供了令人信服的证据，表明PGF2α治疗刺激IRS1丝氨酸磷酸化，这可能导致对IGF-I反应能力减弱。看来，磷酸化事件的快速变化可能是介导PGF2α诱导的黄体退化的早期事件之一。(分子内分泌学24：632-643,2010)
Little is known about the early intracellular events that contribute to corpus luteum regression. Experiments were designed to determine the effects of prostaglandin F2 alpha (PGF2 alpha) on phosphatidylinositol-3-kinase (PI3K)/Akt signaling in the corpus luteum in vivo and in vitro. Treatment of midluteal-phase cows with a luteolytic dose of PGF2 alpha resulted in a rapid increase in ERK and mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K1) signaling and a rapid suppression of Akt phosphorylation in luteal tissue. In vitro treatment of primary cultures of luteal cells with PGF2 alpha also resulted in an increase in ERK and mTOR/p70S6K1 signaling and a diminished capacity of IGF-I to stimulate PI3K, Akt, and protein kinase C zeta activation. Accounting for the reductions in PI3K and Akt activation observed in response to PGF2 alpha treatment, we found that PGF2 alpha promoted the phosphorylation of serine residues (307, 612, 636) in the insulin receptor substrate 1 (IRS1) peptide sequence in vivo and in vitro. Serine phosphorylation of IRS1 was associated with reduced formation of IGF-I-stimulated IRS1/PI3Kp85 complexes. Furthermore, treatment with inhibitors of the MAPK kinase 1/ERK or mTOR/p70S6K1 signaling pathways prevented PGF2 alpha-induced serine phosphorylation of IRS1 and abrogated the inhibitory actions of PGF2 alpha on Akt activation. Taken together, these experiments provide compelling evidence that PGF2 alpha treatment stimulates IRS1 serine phosphorylation, which may contribute to a diminished capacity to respond to IGF-I. It seems likely that the rapid changes in phosphorylation events are among the early events that mediate PGF2 alpha-induced corpus luteum regression. (Molecular Endocrinology 24: 632-643, 2010)