小柯机器人

美国国立癌症研究所Steven D. Cappell团队发现，在S/G2期失去CDK4/6的活性导致细胞周期逆转。相关论文于2023年7月5日在线发表在《自然》杂志上。

研究人员表示，在哺乳动物细胞中，增殖的决定被认为是在细胞周期的限制点不可逆转地做出的，当有丝分裂原信号在细胞周期蛋白A2/细胞周期蛋白依赖性激酶2（CDK2）和视网膜母细胞瘤蛋白之间形成正反馈环。

与这个教科书上的模型相反，研究人员表明，增殖的决定实际上是完全可逆的。相反，研究人员发现所有的循环细胞在没有有丝分裂原的情况下都会退出细胞周期，除非它们先进入有丝分裂并进行分裂。有丝分裂和退出细胞周期这两种命运之间的时间竞争，是因为细胞周期蛋白A2/CDK2的活性在整个细胞周期中取决于CDK4/6的活性，而不仅仅是在G1期。如果没有有丝分裂原，只有当细胞周期蛋白A2的半衰期长到足以维持CDK2在整个G2/M期的活性时，才会观察到有丝分裂。因此，细胞依赖有丝分裂原和CDK4/6活性来维持CDK2活性和视网膜母细胞瘤蛋白在整个间期的磷酸化。因此，如果有丝分裂原信号丢失，即使细胞向有丝分裂进展的过程延迟2小时，也会诱发细胞周期的退出。

这些研究结果揭示了限制点现象的分子机制，揭示了CDK4/6活性在S期和G2期的意外作用，并解释了有丝分裂原信号消失后所有细胞的行为。

附：英文原文

Title: Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal

Author: Cornwell, James A., Crncec, Adrijana, Afifi, Marwa M., Tang, Kristina, Amin, Ruhul, Cappell, Steven D.

Issue&Volume: 2023-07-05

Abstract: In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle1,2, when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and the retinoblastoma protein3,4,5. Contrary to this textbook model, here we show that the decision to proliferate is actually fully reversible. Instead, we find that all cycling cells will exit the cell cycle in the absence of mitogens unless they make it to mitosis and divide first. This temporal competition between two fates, mitosis and cell cycle exit, arises because cyclin A2/CDK2 activity depends upon CDK4/6 activity throughout the cell cycle, not just in G1 phase. Without mitogens, mitosis is only observed when the half-life of cyclin A2 protein is long enough to sustain CDK2 activity throughout G2/M. Thus, cells are dependent on mitogens and CDK4/6 activity to maintain CDK2 activity and retinoblastoma protein phosphorylation throughout interphase. Consequently, even a 2-h delay in a cell’s progression towards mitosis can induce cell cycle exit if mitogen signalling is lost. Our results uncover the molecular mechanism underlying the restriction point phenomenon, reveal an unexpected role for CDK4/6 activity in S and G2 phases and explain the behaviour of all cells following loss of mitogen signalling.

DOI: 10.1038/s41586-023-06274-3

Source: https://www.nature.com/articles/s41586-023-06274-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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