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首页> 外文期刊>Molecular and Cellular Biology >Mitotic Raptor Promotes mTORC1 Activity, G2/M Cell Cycle Progression, and Internal Ribosome Entry Site-Mediated mRNA Translation
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Mitotic Raptor Promotes mTORC1 Activity, G2/M Cell Cycle Progression, and Internal Ribosome Entry Site-Mediated mRNA Translation

机译：有丝分裂的猛禽促进mTORC1活性，G2 / M细胞周期进程和内部核糖体进入位点介导的mRNA翻译。

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The mTOR signaling complex integrates signals from growth factors and nutrient availability to control cell growth and proliferation, in part through effects on the protein-synthetic machinery. Protein synthesis rates fluctuate throughout the cell cycle but diminish significantly during the G2/M transition. The fate of the mTOR complex and its role in coordinating cell growth and proliferation signals with protein synthesis during mitosis remain unknown. Here we demonstrate that the mTOR complex 1 (mTORC1) pathway, which stimulates protein synthesis, is actually hyperactive during mitosis despite decreased protein synthesis and reduced activity of mTORC1 upstream activators. We describe previously unknown G2/M-specific phosphorylation of a component of mTORC1, the protein raptor, and demonstrate that mitotic raptor phosphorylation alters mTORC1 function during mitosis. Phosphopeptide mapping and mutational analysis demonstrate that mitotic phosphorylation of raptor facilitates cell cycle transit through G2/M. Phosphorylation-deficient mutants of raptor cause cells to delay in G2/M, whereas depletion of raptor causes cells to accumulate in G1. We identify cyclin-dependent kinase 1 (cdk1 [cdc2]) and glycogen synthase kinase 3 (GSK3) pathways as two probable mitosis-regulated protein kinase pathways involved in mitosis-specific raptor phosphorylation and altered mTORC1 activity. In addition, mitotic raptor promotes translation by internal ribosome entry sites (IRES) on mRNA during mitosis and is demonstrated to be associated with rapamycin resistance. These data suggest that this pathway may play a role in increased IRES-dependent mRNA translation during mitosis and in rapamycin insensitivity.
机译：mTOR信号复合物整合了来自生长因子和营养物质可利用的信号，以部分地通过对蛋白质合成机制的影响来控制细胞的生长和增殖。蛋白质合成速率在整个细胞周期中波动，但在G 2 / M过渡期间显着降低。 mTOR复合物的命运及其在有丝分裂期间协调细胞生长和增殖信号与蛋白质合成的作用仍然未知。在这里，我们证明了刺激蛋白质合成的mTOR复合物1（mTORC1）途径实际上在有丝分裂期间过度活跃，尽管蛋白质合成减少并且mTORC1上游激活剂的活性降低。我们描述了以前未知的G 2 / M特异的mTORC1，蛋白质猛禽的组件的磷酸化，并证明有丝分裂的猛禽磷酸化改变有丝分裂过程中的mTORC1功能。磷酸肽图谱和突变分析表明，猛禽的有丝分裂磷酸化促进细胞周期通过G 2 / M的转运。猛禽的磷酸化缺陷突变体导致细胞延迟G 2 / M，而猛禽的耗竭导致细胞积累在G 1 中。我们确定细胞周期蛋白依赖性激酶1（cdk1 [cdc2]）和糖原合酶激酶3（GSK3）途径为参与有丝分裂特有的猛禽磷酸化和改变mTORC1活性的两个可能的有丝分裂调控蛋白激酶途径。此外，有丝分裂的猛禽在有丝分裂期间通过mRNA上的内部核糖体进入位点（IRES）促进翻译，并被证明与雷帕霉素抗性有关。这些数据表明该途径可能在有丝分裂期间增加IRES依赖性mRNA翻译和雷帕霉素不敏感性中起作用。

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