SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27
SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27
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DOI：
10.1038/12013
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发表时间：
1999-08-01
影响因子：
21.3
通讯作者：
Pagano, M
中科院分区：
文献类型：
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作者：
Carrano, AC;Eytan, E;Pagano, M
哺乳动物细胞周期蛋白依赖性激酶(CDK)抑制物p27的降解是细胞从静止状态向增殖状态转变所必需的。P27的泛素化和随后的降解依赖于其被细胞周期蛋白-CDK复合体的磷酸化。然而，p27泛素化所必需的泛素蛋白连接酶还没有确定。在这里，我们证明了F-box蛋白Skp2以一种磷酸化依赖的方式特异性识别p27，这是F-box-蛋白质-底物相互作用的特征。此外，在体内和体外，Skp2都是泛素化和降解磷酸化p27的机械的限速元件，因此，p27的降解受到丝裂原刺激后Skp2和细胞周期蛋白的双重控制。
Degradation of the mammalian cyclin-dependent kinase (CDK) inhibitor p27 is required for the cellular transition from quiescence to the proliferative state. The ubiquitination and subsequent degradation of p27 depend on its phosphorylation by cyclin-CDK complexes. However, the ubiquitin-protein ligase necessary for p27 ubiquitination has not been identified. Here we show that the F-box protein SKP2 specifically recognizes p27 in a phosphorylation-dependent manner that is characteristic of an F-box-protein-substrate interaction. Furthermore, both in vivo and in vitro, SKP2 is a rate-limiting component of the machinery that ubiquitinates and degrades phosphorylated p27, Thus, p27 degradation is subject to dual control by the accumulation of both SKP2 and cyclins following mitogenic stimulation.