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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling
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Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

机译：雌二醇17β通过胰岛素样生长因子1信号传导调节小鼠子宫上皮细胞增殖

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摘要

Estradiol-17β (E_2) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor a (ERα). in this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3β (GSK3β) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3β in the absence of E_2 is sufficient to induce uterine epithelial cell proliferation, and GSK3β is epistatic to IGF1 signaling, indicating a linear pathway from E_2 to cyclin D1. Exposure to E_2 is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.
机译：雌二醇-17β（E_2）通过其转录因子受体a（ERα）发出信号，从而导致小鼠和人类子宫上皮细胞增殖。在这项工作中，我们表明该信号是由上皮细胞表达的胰岛素样生长因子1受体（IGF1R）介导的，其活化导致磷酸肌醇3-激酶/蛋白激酶B通路的刺激，从而导致细胞周期蛋白D1核积累并与规范的细胞周期仪合作。细胞周期蛋白D1的核积累是由蛋白激酶B的抑制性磷酸化作用引起的糖原合酶激酶3β（GSK3β）活性的抑制导致的。一旦激活了IGF1途径，对ER信号的抑制就表明它独立于ER。在没有E_2的情况下抑制GSK3β足以诱导子宫上皮细胞增殖，并且GSK3β对IGF1信号具有上位性，表明从E_2到细胞周期蛋白D1的线性途径。暴露于E_2是子宫内膜癌的主要危险因素，这表明该IGF1介导的突变下游激活可能是进展为非ER依赖性肿瘤的原因。

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