Switching ceyclin D-Cdk4 kinase activity on and off
Switching ceyclin D-Cdk4 kinase activity on and off
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DOI：
10.4161/cc.7.7.5637
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发表时间：
2008-04-01
期刊：
影响因子：
4.3
通讯作者：
Blain, Stacy W.
中科院分区：
文献类型：
--
作者：
Blain, Stacy W.
周期蛋白激酶是细胞增殖的主要调控因子。这些丝氨酸/苏氨酸激酶是启动和停止细胞周期以响应增殖或抗增殖信号的马达。它们磷酸化触发有序细胞周期进程所需的底物，因此它们的活性受到严格调节，以防止不适当的激活。细胞外环境和细胞周期机制之间的主要接口之一是细胞周期蛋白cdks与两个化学计量周期蛋白激酶抑制剂（CKIs）家族，Ink4s和Cip/Kips的相互作用。顾名思义，cki历来被认为是cyclin-cdks的负调节因子，负责快速有效地关闭cyclin-cdk活性。然而，细胞周期蛋白D-cdk4与Cip/Kip家族，特别是与p27Kip1的相互作用似乎很复杂。除了抑制细胞周期蛋白D-cdk4的能力外，p27似乎是该复合物所需的组装因子，至少在某些时候以非抑制性模式结合。p27是否是cyclin D-cdk4/6抑制剂存在争议，它如何在这两种模式之间切换也不得而知。为了论证双态机制，我们最近表明p27既可以是cdk4结合抑制剂，也可以是cdk4结合非抑制剂，这取决于细胞的生长状态。这一观点强调了这一发现在正常细胞周期进展和肿瘤发展方面的重要性。
The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extracellular environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, we have recently shown that p27 can be both a cdk4 bound-inhibitor and a bound-non-inhibitor, depending on the growth state of the cell. This perspective highlights the significance of this finding in terms of normal cell cycle progression and tumor development.