Rb inactivation in cell cycle and cancer The puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase
Rb inactivation in cell cycle and cancer The puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase
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DOI：
10.4161/cc.9.4.10611
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发表时间：
2010-02-15
期刊：
影响因子：
4.3
通讯作者：
Roger, Pierre P.
中科院分区：
文献类型：
--
作者：
Paternot, Sabine;Bockstaele, Laurence;Roger, Pierre P.
细胞周期蛋白依赖性激酶(CDK)4是一个主整合因子，它将促有丝分裂/致癌信号通路与中央肿瘤抑制因子Rb失活和细胞周期结合在一起。它的激活需要与D型细胞周期蛋白结合，然后由动物细胞中唯一已知的CDK激活蛋白-细胞周期蛋白H-CDK7在T172处进行T-环磷酸化。与观察到的细胞周期蛋白H-CDK7的结构活性不同，我们最近发现细胞周期蛋白D结合的CDK4的T172-磷酸化是一个重要的细胞周期调控靶点。有趣的是，CDK6的同源T177-磷酸化在几个系统中都很弱，不存在这种调节。从这个角度出发，我们综述了导致D型细胞周期蛋白-CDK4复合体激活的多步机制的最新进展和争论。这涉及到重新评估Cip/Kip CDK“抑制物”和CDK7在这一过程中的意义。
Cyclin-dependent kinase (CDK) 4 is a master integrator that couples mitogenic/oncogenic signalling cascades with the inactivation of the central oncosuppressor Rb and the cell cycle. Its activation requires binding to a D-type cyclin and then T-loop phosphorylation at T172 by the only identified CDK-activating kinase in animal cells, cyclin H-CDK7. In contrast with the observed constitutive activity of cyclin H-CDK7, we have recently identified the T172-phosphorylation of cyclin D-bound CDK4 as a crucial cell cycle regulatory target. Intriguingly, the homologous T177-phosphorylation of CDK6 is weak in several systems and does not present this regulation. In this Perspective, we review the recent advances and debates on the multistep mechanism leading to activation of D-type cyclin-CDK4 complexes. This involves a re-evaluation of the implication of Cip/Kip CDK "inhibitors" and CDK7 in this process.