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首页> 外文期刊>Cell cycle >Why minimal is not optimal: Driving the mammalian cell cycle - and drug discovery - with a physiologic CDK control network
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Why minimal is not optimal: Driving the mammalian cell cycle - and drug discovery - with a physiologic CDK control network

机译：为什么最小化不是最佳选择：利用生理性CDK控制网络驱动哺乳动物细胞周期-和药物开发

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摘要

Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G 1/S transition and for efforts to target Cdk2 therapeutically in human cancers.
机译：真核细胞分裂周期的进展受细胞周期蛋白依赖性激酶（CDK）活性的支配。为了使CDK变得活跃，它必须（1）结合阳性调节亚基（cyclin），并且（2）在其激活（T）环上被磷酸化。在后生动物中，多个CDK催化亚基（各自具有一组不同的优选细胞周期蛋白伴侣）调节细胞周期，但很难在体内为单个CDK赋予功能。生化分析和优势阴性等位基因实验表明，特定的CDK /细胞周期蛋白复合物调节不同的事件，但是单独或组合使用的相间CDK（Cdk2，-4和-6）的遗传损失并不能阻止培养细胞的增殖。这些敲除和敲除研究表明，CDK网络内置了冗余或可塑性，但没有解决在完整CDK补充的正常细胞中是否存在真正的冗余。在这里，我们讨论了最近的工作，该工作采用化学遗传方法来揭示，当维持正常细胞周期蛋白配对时，遗传上非必需的CDK Cdk2的活性是细胞增殖所必需的。这些结果对细胞周期的系统级组织，限制点和G 1 / S过渡的调节以及在人类癌症中治疗性靶向Cdk2的努力都有影响。

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