Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy
Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy
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DOI：
10.1210/en.2009-0419
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发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Lye, Stephen
中科院分区：
文献类型：
--
作者：
Jaffer, Shabana;Shynlova, Oksana;Lye, Stephen
妊娠期间子宫的适应性生长涉及细胞表型的逐渐变化，从细胞肥大的早期增殖阶段到细胞肥大的中期合成阶段，最终达到收缩/分娩表型。哺乳动物靶标雷帕霉素(MTOR)信号通路在许多组织中调节细胞的生长和增殖。我们假设mTOR是妊娠期激素启动的子宫肌层增生的中介物。分析正常妊娠大鼠胚胎中mTOR及其上游调节因子[胰岛素受体底物-1、磷脂酰肌醇-3-激酶(PI3K)、Akt]和下游效应因子[S6-Kinase-1(S6K1)和eI4Fe结合蛋白1(4EBP1)]的蛋白表达和磷酸化水平。此外，我们还利用去卵巢(OVX)大鼠模型分析了雌二醇单独及联合mTOR特异性抑制剂雷帕霉素对子宫肌细胞mTOR通路和增殖活性的调节作用。我们的结果表明，在妊娠增殖期，胰岛素受体底物-1蛋白水平和PI3K、mTOR和S6K1的磷酸化(激活)形式在大鼠子宫肌层中显著上调。雌激素治疗OVX大鼠导致IGF-I一过性升高，随后PI3K/mTOR通路上调，这通过一系列磷酸化反应(P-P85、P-Akt、P-mTOR、P-S6K1和P-4EBP1)变得明显。雷帕霉素阻断去卵巢大鼠子宫肌层P-mTOR、P-S6K1和P-4EBP1蛋白的激活，并显著减少子宫肌层中增殖细胞的数量。我们在体内的数据表明，雌二醇能够激活子宫肌细胞中的PI3K/mTOR信号通路，并提示这种激活与妊娠早期子宫肌层增生的诱导有关。(内分泌学150：4672-4680,2009)
The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin ( mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated ( activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation. (Endocrinology 150: 4672-4680, 2009)