Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation

被引：107

作者：

Higa, LA ^{[1
]}

Yang, XM ^{[1
]}

Zheng, JY ^{[1
]}

Banks, D ^{[1
]}

Wu, M ^{[1
]}

Ghosh, P ^{[1
]}

Sun, H ^{[1
]}

Zhang, H ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA

来源：

CELL CYCLE | 2006年 / 5卷 / 01期

关键词：

CUL4; Dacapo; p27(Kip1); cyclin E; SCF; proteolysis;

D O I：

10.4161/cc.5.1.2266

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：71 / 77

页数：7

共 49 条

[1] Kip1 meets SKP2: new links in cell-cycle control [J].