Zhu Liyin, Pollard Jeffrey W
Department of Developmental and Molecular Biology, Center of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15847-51. doi: 10.1073/pnas.0705749104. Epub 2007 Sep 25.
Estradiol-17beta (E(2)) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor alpha (ERalpha). 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 3beta (GSK3beta) 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 GSK3beta in the absence of E(2) is sufficient to induce uterine epithelial cell proliferation, and GSK3beta 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.
17β-雌二醇（E₂）通过其转录因子受体α（ERα）信号传导，致使小鼠和人类子宫上皮细胞增殖。在本研究中，我们发现这种信号传导由上皮细胞中表达的胰岛素样生长因子1受体（IGF1R）介导，其激活会刺激磷酸肌醇3激酶/蛋白激酶B通路，进而导致细胞周期蛋白D1在细胞核内积聚，并与经典细胞周期机制相互作用。这种细胞周期蛋白D1在细胞核内积聚是由于蛋白激酶B的抑制性磷酸化导致糖原合酶激酶3β（GSK3β）活性受到抑制。一旦IGF1通路被激活，对ER信号传导的抑制表明其独立于ER。在没有E₂的情况下抑制GSK3β足以诱导子宫上皮细胞增殖，并且GSK3β对IGF1信号传导具有上位性作用，表示从E₂到细胞周期蛋白D1存在一条线性通路。接触E₂是子宫内膜癌的主要危险因素，这表明该IGF1介导通路的下游因突变而激活可能是导致向ER非依赖性肿瘤进展的原因。
