L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes
L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes
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DOI：
10.4161/cc.5.15.3150
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发表时间：
2006-08-01
期刊：
影响因子：
4.3
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
--
作者：
Banks, Damon;Wu, Min;Zhang, Hui
CUL 4-ROC 1 E3连接酶复合物调节基因组稳定性、复制和细胞周期进程。一种新的含WD 40结构域的蛋白，L2 DTL/CDT 2和PCNA被鉴定为与CUL 4/DDB 1复合物相关的蛋白。CUL 4A、L2 DTL、PCNA、DDB 1或ROC 1的失活诱导p53稳定和生长停滞。L2 DTL、PCNA和DDB 1/CUL 4A复合物与p53肿瘤抑制因子及其调节因子MDM 2/HDM 2相互作用。分离的CUL 4A复合物显示出对p53的有效和稳健的聚泛素化活性，并且该活性依赖于L2 DTL、PCNA、DDB 1、ROC 1和MDM 2/HDM 2。我们还发现p53和CUL 4复合物之间的相互作用受DNA损伤的调节。我们的数据进一步表明，MDM 2/HDM 2在紫外线照射下迅速蛋白水解，这一过程受到CUL 4/DDB 1和PCNA的调节。我们的研究表明，PCNA，L2 DTL和DDB 1-CUL 4A复合物在调节非应激和应激细胞中p53和MDM 2/HDM 2的蛋白稳定性方面发挥关键和不同的作用。
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.