p53 mediates the negative regulation of MDM2 by orphan receptor TR3
p53 mediates the negative regulation of MDM2 by orphan receptor TR3
复制标题
p53 通过孤儿受体 TR3 介导 MDM2 的负向调节
DOI：
10.1038/sj.emboj.7601435
复制
发表时间：
2006-12
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
MDM2是一种癌蛋白，其转化潜能通过过表达而被激活。MDM2的表达水平受孤儿受体TR3负调控，TR3主要作为转录因子调节基因表达。然而，基本机制在很大程度上尚不清楚。在这里，我们提出了第一个证据，TR3对MDM 2的抑制是由p53介导的。我们发现，TR3直接与p53相互作用，但不与MDM2相互作用，这种相互作用对于TR3抑制MDM2表达至关重要。TR3通过阻断其乙酰化下调p53转录活性，导致MDM2转录水平降低。此外，TR3与p53的结合阻碍了MDM 2诱导的p53的泛素化和降解，导致MDM 2的泛素化和降解。此外，TR 3还可以增强紫外线照射诱导的p53介导的细胞凋亡。总之，我们的研究结果表明，p53在转录和转录后水平介导TR3对MDM2的抑制，并表明TR3是开发限制MDM2诱导的肿瘤进展的新抗癌药物的潜在靶点。
MDM2 is an oncoprotein whose transforming potential is activated by overexpression. The expression level of MDM2 is negatively regulated by orphan receptor TR3 that mainly acts as a transcriptional factor to regulate gene expression. However, the underlying mechanism is largely unclear. Here, we present the first evidence that inhibition of TR3 on MDM2 is mediated by p53. We found that TR3 directly interacts with p53 but not MDM2, and such interaction is critical for TR3 to inhibit MDM2 expression. TR3 downregulates p53 transcriptional activity by blocking its acetylation, leading to a decrease on the transcription level of MDM2. Furthermore, TR3 binding to p53 obstructs its ubiquitination and degradation induced by MDM2, resulting in the MDM2 ubiquitination and degradation. In addition, TR3 could enhance p53‐mediated apoptosis induced by UV irradiation. Taken together, our findings demonstrate that p53 mediates the suppression of TR3 on MDM2 at both transcriptional and post‐transcriptional level and suggest TR3 as a potential target to develop new anticancer agents that restrict MDM2‐induced tumor progression.
登录
查看更多内容
影响因子：
11.4
作者：
Roth, J;Dobbelstein, M;Levine, AJ
通讯作者：
Levine, AJ
影响因子：
4
作者：
Xiao-feng Lin;Bi-xing Zhao;Hang Chen;Xiao-feng Ye;Chao-yi Yang;Hai-Ying Zhou;Ming-qing Zhang;Sheng-Cai Lin;Qiao Wu
通讯作者：
Xiao-feng Lin;Bi-xing Zhao;Hang Chen;Xiao-feng Ye;Chao-yi Yang;Hai-Ying Zhou;Ming-qing Zhang;Sheng-Cai Lin;Qiao Wu
影响因子：
11.4
作者：
Wang, CG;Ivanov, A;Chen, JD
通讯作者：
Chen, JD
影响因子：
4.8
作者：
Gostissa, M;Morelli, M;Del Sal, G
通讯作者：
Del Sal, G
影响因子：
64.5
作者：
Avantaggiati, ML;Ogryzko, V;Kelly, K
通讯作者：
Kelly, K