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首页> 外文期刊>Cellular Signalling >Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1
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Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1

机译:在C2C12成肌细胞中抑制雷帕霉素(mTOR)信号转导的哺乳动物靶点可防止成肌分化,而不影响4E-BP1的过度磷酸化

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摘要

Current accepted models suggest that hypophosphorylated 4E-binding protein (4E-BP1) binds to initiation factor 4E (elF4E) to inhibit cap-dependent translation, a process readily reversed by its phosphorylation following activation of mammalian target of rapamycin (mTORC1) signalling. Myogenic differentiation in the C2C12 myoblast model system reflects a concerted and controlled activation of transcription and translation following the exit of cells from the cell cycle. Here we show that myogenic differentiation is associated with increased rates of translation, the up-regulation of both 4E-BP1 mRNA and protein levels and enhanced levels of elF4E/4E-BP1 complex. Paradoxically, treatment of C2C12 myoblasts with an inhibitor of mTOR signalling (RAD001) which inhibits translation, promotes the hyperphosphorylation of 4E-BP1 on novel sites and prevents the increase in 4E-BP1 levels. In contrast, elF4E appears to be under translational control with a significant delay between induction of mRNA and subsequent protein expression.
机译:当前公认的模型表明,低磷酸化的4E结合蛋白(4E-BP1)与起始因子4E(elF4E)结合,以抑制帽依赖性翻译,该过程很容易被哺乳动物雷帕霉素靶标(mTORC1)信号激活后的磷酸化逆转。 C2C12成肌细胞模型系统中的成肌分化反映了细胞退出细胞周期后转录和翻译的协调一致和受控的激活。在这里,我们显示肌源性分化与翻译率增加,4E-BP1 mRNA和蛋白水平的上调以及eIF4E / 4E-BP1复合物水平的提高有关。矛盾的是,用抑制翻译,促进新位点上4E-BP1的过度磷酸化并阻止4E-BP1水平升高的mTOR信号抑制剂(RAD001)处理C2C12成肌细胞。相反,eIF4E似乎处于翻译控制之下,在诱导mRNA和随后的蛋白表达之间存在明显的延迟。

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