Decidual mechanistic target of rapamycin (mTOR) is inhibited, amino acid response (AAR) and protein kinase CK2 are activated, and IGF (insulin-like growth factor) binding protein (IGFBP)-1 is hyperphosphorylated in human intrauterine growth restriction (IUGR). Using decidualized human immortalized endometrial stromal cells (HIESC), we hypothesized that hypoxia and leucine deprivation causing inhibition of decidual IGF-1 signaling is mediated by mTOR, AAR, CK2 and IGFBP-1 phosphorylation. Mass spectrometry demonstrated that hypoxia (1% O2) or rapamycin increased IGFBP-1 phosphorylation singly at Ser101/119/169 (confirmed using immunoblotting) and dually at pSer169 + 174. Hypoxia resulted in mTOR inhibition, AAR and CK2 activation, and decreased IGF-1 bioactivity, with no additional changes with rapamycin + hypoxia. Rapamycin and/or hypoxia promoted colocalization of IGFBP-1 and CK2 (dual-immunofluorescence and proximity ligation assay). Leucine deprivation showed similar outcomes. Changes in IGFBP-1 phosphorylation regulated by mTOR/AAR signaling and CK2 may represent a novel mechanism linking oxygen and nutrient availability to IGF-1 signaling in the decidua.

中文翻译：

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响应低氧和亮氨酸剥夺的蜕膜IGF-1信号的抑制是通过mTOR和AAR途径以及增加的IGFBP-1磷酸化介导的。

雷帕霉素（mTOR）的决定性机制靶点被抑制，氨基酸应答（AAR）和蛋白激酶CK2被激活，并且IGF（胰岛素样生长因子）结合蛋白（IGFBP）-1在人子宫内生长受限（IUGR）中被过度磷酸化。使用蜕膜化的人类永生化子宫内膜基质细胞（HIESC），我们假设低氧和亮氨酸剥夺导致蜕膜IGF-1信号的抑制是由mTOR，AAR，CK2和IGFBP-1磷酸化介导的。质谱分析表明，低氧（1％O2）或雷帕霉素分别在Ser101 / 119/169（通过免疫印迹证实）和在pSer169 + 174双重增加IGFBP-1磷酸化。 -1生物活性，雷帕霉素+缺氧无其他变化。雷帕霉素和/或低氧促进了IGFBP-1和CK2的共定位（双重免疫荧光和邻近结扎法）。亮氨酸剥夺显示出相似的结果。由mTOR / AAR信号和CK2调节的IGFBP-1磷酸化的变化可能代表了一种新的机制，将蜕膜中的氧气和养分利用率与IGF-1信号联系起来。