Adenoviral E1A targets mdm4 to stabilize tumor suppressor p53
Adenoviral E1A targets mdm4 to stabilize tumor suppressor p53
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DOI：
10.1158/0008-5472.can-04-2419
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Hung, MC
中科院分区：
文献类型：
--
作者：
Li, Z;Day, CP;Hung, MC
腺病毒蛋白E1a具有多种抗癌活性，包括稳定p53抑癌基因，并已在临床试验中通过基因治疗方法进行了测试。为了鉴定与E1a的抗癌活性相关的潜在E1a结合蛋白，我们筛选了酵母双杂交文库，并将MDM2相关的P53结合蛋白Mdm4鉴定为一个新的E1a结合蛋白。Mdm4的NH2末端区域和E1a的CR1结构域是E1a与Mdm4相互作用所必需的。E1a优先结合MDM4而不是MDM2，并在Mdm4存在的情况下与P53形成复合体，导致P53以p14(ARF)非依赖的方式稳定。在缺乏Mdm4的情况下，E1a不能稳定P53，表明Mdm4是E1a稳定P53所必需的。此外，E1a介导的P53在细胞核内稳定。虽然E1a对P53-MDM2的相互作用没有影响，但它促进了Mdm4与P53的结合，并抑制了MDM2与Mdm4的结合，导致了P53的核外向减少。因此，我们的发现强调了一种新的机制，即E1a通过MDM4稳定P53肿瘤抑制因子。
The adenoviral protein E1A associates with multiple anticancer activities, including stabilization of p53 tumor suppressor, and has been tested through gene therapy approaches in clinical trials. To identify potential E1A-binding proteins involved in E1A's anticancer activities, we screened a yeast two-hybrid library and identified Mdm4, an Mdm2-related p53-binding protein, as a novel E1A-binding protein. The NH2-terminal region of Mdm4 and the CR1 domain of E1A were required for the interaction between E1A and Mdm4. E1A preferentially bound to Mdm4 rather than Mdm2 and formed a complex with p53 in the presence of Mdm4, resulting in the stabilization of p53 in a p14(ARF)-independent manner. E1A failed to stabilize p53 in the absence of Mdm4, showing that Mdm4 was required for p53 stabilization by E1A. Moreover, E1A-mediated stabilization of p53 occurred in nucleus. Although it had no effect on the p53-Mdm2 interaction, E1A facilitated Mdm4 binding to p53 and inhibited Mdm2 binding to Mdm4, resulting in decreased nuclear exportation of p53. Thus, our findings highlighted a novel mechanism, whereby E1A stabilized the p53 tumor suppressor through Mdm4.