Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation
Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation
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DOI：
10.4161/cc.5.1.2266
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发表时间：
2006-01-01
期刊：
影响因子：
4.3
通讯作者：
Zhang, H
中科院分区：
文献类型：
--
作者：
Higa, LA;Yang, XM;Zhang, H
CUL4 （cullin 4）蛋白是一类调节复制和转录的新泛素E3连接酶的核心成分。为了研究CUL4在细胞周期调控中的作用，我们分析了CUL4失活对果蝇和人类细胞的影响。我们发现，果蝇细胞中CUL4的缺失会导致G(1)细胞周期阻滞和CDK抑制剂Dacapo蛋白水平升高。Dacapo与CUL4的共消除可消除G(1)细胞周期阻滞。在人类细胞中，CUL4A的失活诱导CDK抑制剂P27（Kip1）稳定和G(1)细胞周期阻滞，这依赖于P27的存在，表明这一调控途径是进化保守的。此外，我们发现果蝇CUL4也独立于Dacapo调控cyclin E的蛋白水平。我们提供的证据表明，人类CUL4B，人类CUL4A的一个类似物，参与了周期蛋白E的调节。CUL4B的缺失导致细胞周期蛋白E的积累，而p27却没有随之增加。人类CUL4B和细胞周期蛋白E也相互作用，CUL4B复合物可以多泛素化CUL4B相关的细胞周期蛋白E。我们的研究表明，在果蝇和人类细胞中，含有cul4的泛素E3连接酶在调节G(1)细胞周期进程中发挥关键作用。
The CUL4 (cullin 4) proteins are the core components of a new class of ubiquitin E3 ligases that regulate replication and transcription. To examine the roles of CUL4 in cell cycle regulation, we analyzed the effect of inactivation of CUL4 in both Drosophila and human cells. We found that loss of CUL4 in Drosophila cells causes G(1) cell cycle arrest and an increased protein level of the CDK inhibitor Dacapo. Coelimination of Dacapo with CUL4 abolishes the G(1) cell cycle arrest. In human cells, inactivation of CUL4A induces CDK inhibitor P27(Kip1) stabilization and G(1) cell cycle arrest which is dependent on the presence of p27, suggesting that this regulatory pathway is evolutionarily conserved. In addition, we found that the Drosophila CUL4 also regulates the protein level of cyclin E independent of Dacapo. We provide evidence that human CUL4B, a paralogue of human CUL4A, is involved in cyclin E regulation. Loss of CUL4B causes the accumulation of cyclin E without a concomitant increase of p27. The human CUL4B and cyclin E proteins also interact with each other and the CUL4B complexes can polyubiquitinate the CUL4B-associated cyclin E. Our studies suggest that the CUL4-containing ubiquitin E3 ligases play a critical role in regulating G(1) cell cycle progression in both Drosophila and human cells.