INHIBITION OF CYCLIN-DEPENDENT KINASES BY P21
INHIBITION OF CYCLIN-DEPENDENT KINASES BY P21
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DOI：
10.1091/mbc.6.4.387
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发表时间：
1995-04-01
影响因子：
3.3
通讯作者：
WEI, N
中科院分区：
文献类型：
--
作者：
HARPER, JW;ELLEDGE, SJ;WEI, N
P21(Cip1)是一种细胞周期蛋白依赖性激酶(CDK)抑制物，可被P53转录激活以应对DNA损伤。我们已经探索了p21与目前已知的CDK的相互作用。P21能有效地抑制CDK2、CDK3、CDK4和CDK6激酶(K-I 0.5-15 nM)，但对CDc2/Cyclin B(K-I类似于400 nM)和CDk5/p35(K-I和gt；2µM)的抑制作用较弱，与CDK7/Cyclin H无关。因此，p21不是CDK的通用抑制剂，但对G1/S CDK/细胞周期蛋白复合体具有选择性。细胞周期蛋白结合大大增强了p21与CDKs的结合。这一特性被结构相关的抑制物p27所共享，这表明了一种共同的生化抑制机制。对于cdk2和cdk4复合体，p27具有p21的抑制效力，但具有略有不同的激酶特异性。在正常的二倍体成纤维细胞中，绝大多数活性的CDK2与p21相关，但这种活性的激酶可以被外源的p21完全抑制。利用纯化组分的重建实验表明，多个p21分子可以与CDK/Cyclin复合体结合，而非活性复合体包含多个p21分子。综上所述，这些数据提出了一种模型，在该模型中，p21作为抑制性缓冲区发挥作用，其水平决定了细胞周期进展所需的激酶活性阈值。
p21(Cip1) is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (K-i 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (K-i similar to 400 nM) and Cdk5/p35 (K-i > 2 mu M), and does not associate with Cdk7/cyclin H. Overexpression of p21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is greatly enhanced by cyclin binding. This property is shared by the structurally related inhibitor p27, suggesting a common biochemical mechanism for inhibition. With respect to Cdk2 and Cdk4 complexes, p27 shares the inhibitory potency of p21 but has slightly different kinase specificities. In normal diploid fibroblasts, the vast majority of active Cdk2 is associated with p21, but this active kinase can be fully inhibited by addition of exogenous p21. Reconstruction experiments using purified components indicate that multiple molecules of p21 can associate with Cdk/cyclin complexes and inactive complexes contain more than one molecule of p21. Together, these data suggest a model whereby p21 functions as an inhibitory buffer whose levels determine the threshold kinase activity required for cell cycle progression.