L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes

被引：113
作者：
Banks, Damon
Wu, Min
Higa, Leigh Ann
Gavrilova, Nadia
Quan, Junmin
Ye, Tao
Kobayashi, Ryuji
Sun, Hong
Zhang, Hui
机构：
[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA
[2] Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Shenzhen, Peoples R China
[3] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Kowloon, Hong Kong, Peoples R China
[4] Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA
来源：
CELL CYCLE | 2006年 / 5卷 / 15期
关键词：
CUL4; DDB1; p53; MDM2/HDM2; PCNA; L2DTL/CDT2; proteolysis;
D O I：
10.4161/cc.5.15.3150
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
The CUL4-ROC1 E3 ligase complex regulates genome stability, replication and cell cycle progression. A novel WD40 domain-containing protein, L2DTL/CDT2 and PCNA were identified as proteins associated with CUL4/DDB1 complexes. Inactivation of CUL4A, L2DTL, PCNA, DDB1 or ROC1 induced p53 stabilization and growth arrest. L2DTL, PCNA and DDB1/CUL4A complexes were found to physically interact with p53 tumor suppressor and its regulator MDM2/HDM2. The isolated CUL4A complexes display potent and robust polyubiquitination activity towards p53 and this activity is dependent on L2DTL, PCNA, DDB1, ROC1 and MDM2/HDM2. We also found that the interaction between p53 and CUL4 complex is regulated by DNA damage. Our data further showed that MDM2/HDM2 is rapidly proteolyzed in response to UV irradiation and this process is regulated by CUL4/DDB1 and PCNA. Our studies demonstrate that PCNA, L2DTL and the DDB1-CUL4A complex play critical and differential roles in regulating the protein stability of p53 and MDM2/HDM2 in unstressed and stressed cells.
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收藏
页码：1719 / 1729
页数：11
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