Mammalian interphase cdks: dispensable master regulators of the cell cycle.
Mammalian interphase cdks: dispensable master regulators of the cell cycle.
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DOI：
10.1177/1947601913479799
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发表时间：
2012-11-01
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影响因子：
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通讯作者：
Enders, Greg H
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作者：
Enders, Greg H
细胞周期蛋白依赖性激酶（Cdks）在所有真核生物中驱动细胞周期进程。酵母具有一种主要的Cdk，它通过与不同的细胞周期蛋白结合来介导不同的细胞周期转换。哺乳动物中与之最接近的同源物Cdk1驱动有丝分裂。哺乳动物还有其他的Cdks——Cdk2、Cdk4和Cdk6，它们是在间期被激活的主要Cdks（间期Cdks，iCdks）。大量证据表明，iCdks的激活决定了间期的进展。然而明显矛盾的是，在基因敲除小鼠中，每种单独的iCdk的缺失分别被证明与活产以及在某些情况下的生育能力是相容的。此外，在小鼠胚胎中可以只有Cdk1作为唯一有功能的Cdk。因此，对于哺乳动物细胞周期进程来说，没有一种iCdks是绝对必需的，这就增加了Cdk1是间期主要调节因子的可能性。然而，iCdks的缺失伴随着细胞周期蛋白与Cdk1结合的重大变化，这表明其功能增强。经过大量调整，一种化学遗传学方法最近能够在不显著扭曲细胞周期蛋白/Cdk复合物形成的情况下检测Cdk2活性急性抑制的影响。结果表明，当以其正常水平表达时，Cdk2在驱动人类细胞进入S期以及维持基因组稳定性方面发挥着关键作用。这些新发现似乎使细胞周期领域恢复了秩序，使其完全回到了iCdks确实起重要作用的观点。它们还强调了基因敲低和基因敲除方法的注意事项，即蛋白质表达不足会显著扰乱蛋白质相互作用网络。我们讨论了这种新的综合观点对未来细胞周期研究以及基于抗Cdk的癌症和其他疾病治疗的影响。
Cyclin-dependent kinases (Cdks) drive cell cycle progression in all eukaryotes. Yeasts have a single major Cdk that mediates distinct cell cycle transitions via association with different cyclins. The closest homolog in mammals, Cdk1, drives mitosis. Mammals have additional Cdks-Cdk2, Cdk4, and Cdk6-that represent the major Cdks activated during interphase (iCdks). A large body of evidence has accrued that suggests that activation of iCdks dictates progression though interphase. In apparent contradiction, deficiency in each individual iCdk, respectively, in knockout mice proved to be compatible with live birth and in some instances fertility. Moreover, murine embryos could be derived with Cdk1 as the only functional Cdk. Thus, none of the iCdks is strictly essential for mammalian cell cycle progression, raising the possibility that Cdk1 is the dominant regulator in interphase. However, an absence of iCdks has been accompanied by major shifts in cyclin association to Cdk1, suggesting gain in function. After considerable tweaking, a chemical genetic approach has recently been able to examine the impact of acute inhibition of Cdk2 activity without marked distortion of cyclin/Cdk complex formation. The results suggest that, when expressed at its normal levels, Cdk2 performs essential roles in driving human cells into S phase and maintaining genomic stability. These new findings appear to have restored order to the cell cycle field, bringing it full circle to the view that iCdks indeed play important roles. They also underscore the caveat in knockdown and knockout approaches that protein underexpression can significantly perturb a protein interaction network. We discuss the implications of the new synthesis for future cell cycle studies and anti-Cdk-based therapy of cancer and other diseases.