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首页> 外文期刊>Cell cycle >Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation.
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Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation.

机译：CUL4泛素E3连接酶参与调节CDK抑制剂Dacapo / p27Kip1和细胞周期蛋白E降解。

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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.
机译：CUL4（cullin 4）蛋白是调节复制和转录的新型泛素E3连接酶的核心成分。为了检查CUL4在细胞周期调控中的作用，我们分析了果蝇和人类细胞中CUL4失活的影响。我们发现果蝇细胞中CUL4的丢失会导致G（1）细胞周期停滞和CDK抑制剂Dacapo的蛋白质水平升高。 Dacapo与CUL4的共消除消除了G（1）细胞周期停滞。在人类细胞中，CUL4A的失活诱导CDK抑制剂p27（Kip1）稳定和G（1）细胞周期停滞，这取决于p27的存在，表明该调节途径在进化上是保守的。此外，我们发现果蝇CUL4还调节细胞周期蛋白E的蛋白水平，而与Dacapo无关。我们提供证据，人类CUL4B，人类CUL4A的旁系同源物，参与细胞周期蛋白E调控。 CUL4B的丢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蛋白也可以相互作用，并且CUL4B复合物可以使CUL4B相关的细胞周期蛋白E泛素化。我们的研究表明，含CUL4的泛素E3连接酶在调节G（1）细胞周期过程中起着关键作用。果蝇和人类细胞。

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