Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.
Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry.
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DOI：
10.1016/j.cell.2016.05.077
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发表时间：
2016-06-30
期刊：
影响因子：
64.5
通讯作者：
Meyer T
中科院分区：
文献类型：
--
作者：
Cappell SD;Chung M;Jaimovich A;Spencer SL;Meyer T
在复制DNA和分裂之前，增殖的细胞必须跨过一个不归路。这种承诺决定在癌症和退行性疾病中起着重要作用，并被认为是通过视网膜母细胞瘤(RB)蛋白的磷酸化来调节的。在这里，我们证明了后期促进复合体/环体(APCCDh1)的失活具有作为细胞周期进入的不返回点的必要特征。我们的研究表明，APCCDh1失活是一种快速、双稳态的开关，在DNA复制开始前不久由Cyclin E/CDK2启动，并由EMI1不可逆。在Rb磷酸化和APCCDh1失活之间的压力下，但不是在APCCDh1失活之后，细胞恢复到丝裂原敏感的静止状态，随后它们可以重新进入细胞周期。因此，APCCDh1失活是细胞失去回到静止状态并决定在细胞周期中前进的承诺点。对细胞周期报告器的实时细胞成像显示，细胞进入细胞周期的时间比限制点晚得多，在此期间有一段时间窗口，在这段时间内，细胞可以返回到静止状态，而不是在周期中前进。
Proliferating cells must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of retinoblastoma (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclo-some (APCCdh1) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APCCdh1 inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APCCdh1 inactivation, but not after APCCdh1 inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APCCdh1 inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle. Live cell imaging of cell-cycle reporters, reveals that cells commit to cell-cyclem, entry much later than the restriction point, and that there’s a window of time during, which a cell can return to quiescence, rather than moving forward through the, cycle.
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