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首页> 外文期刊>Cell cycle >Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells
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Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells

机译：高丝分裂驱动与衰老细胞中的有丝分裂无能共存

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When the cell cycle is arrested, even though growth-promoting pathways such as mTOR are still active, then cells senesce. For example, induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR, which, in turn, converts p21/p16-induced arrest into senescence (geroconversion). Here we show that geroconversion is accompanied by dramatic accumulation of cyclin D1 followed by cyclin E and replicative stress. When p21 was switched off, senescent cells (despite their loss of proliferative potential) progressed through S phase, and levels of cyclins D1 and E dropped. Most cells entered mitosis and then died, either during mitotic arrest or after mitotic slippage, or underwent endoreduplication. Next, we investigated whether inhibition of mTOR would prevent accumulation of cyclins and loss of mitotic competence in p21-arrested cells. Both nutlin-3, which inhibits mTOR in these cells, and rapamycin suppressed geroconversion during p21- induced arrest, decelerated accumulation of cyclins D1 and E and decreased replicative stress. When p21 was switched off, cells successfully progressed through both S phase and mitosis. Also, senescent mouse embryonic fibroblasts (MEFs) overexpressed cyclin D1. After release from cell cycle arrest, senescent MEFs entered S phase but could not undergo mitosis and did not proliferate. We conclude that cellular senescence is characterized by futile hyper-mitogenic drive associated with mTOR-dependent mitotic incompetence.
机译：当细胞周期停止时，即使诸如mTOR的促进生长的途径仍然活跃，细胞也会衰老。例如，对p21或p16的诱导会在不抑制mTOR的情况下终止细胞周期，从而将p21 / p16诱导的阻止转变为衰老（基因转化）。在这里，我们表明，转基因伴随着细胞周期蛋白D1的急剧积累，接着是细胞周期蛋白E和复制应激。当关闭p21时，衰老细胞（尽管其增殖能力丧失）发展到S期，而细胞周期蛋白D1和E的水平下降。大多数细胞进入有丝分裂，然后在有丝分裂停止期间或有丝分裂滑移后死亡，或经历了核内复制。接下来，我们研究了抑制mTOR是否会阻止p21阻滞细胞中细胞周期蛋白的积累和有丝分裂能力的丧失。可以在这些细胞中抑制mTOR的nutlin-3和雷帕霉素都可以抑制p21诱导的阻滞过程中的神经转化，减缓细胞周期蛋白D1和E的积累并降低复制压力。当p21关闭时，细胞成功地通过了S期和有丝分裂。此外，衰老的小鼠胚胎成纤维细胞（MEF）过度表达细胞周期蛋白D1。从细胞周期停滞释放后，衰老的MEF进入S期，但不能发生有丝分裂，也不会增殖。我们得出结论，细胞衰老的特征在于与mTOR依赖的有丝分裂无能相关的无用的超有丝分裂驱动。

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