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Involvement of CUL4 Ubiquitin E3 Ligases in Regulating CDK Inhibitors Dacapo/p27Kip1 and Cyclin E Degradation
Leigh Ann Higa, Xiaoming Yang, Jianyu Zheng, Damon Banks, Min Wu, Papia Ghosh, Hong Sun and Hui Zhang
volume 5 | issue 1
1 january 2006Pages: 71 - 77
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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 G1 cell cycle arrest and an increased protein level of the CDK inhibitor Dacapo. Co-elimination of Dacapo with CUL4 abolishes the G1 cell arrest. In human cells, inactivation of CUL4A induces CDK inhibitor p27Kip1 stabilization and G1 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 plays a critical role in regulating G1 cell cycle progression in both Drosophila and human cells.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.