Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7
Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7
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泛素 E3 连接酶 MARCH7 对 Mdm2-p53 通路的调节
DOI：
10.15252/embr.201744465
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发表时间：
2018-02-01
期刊：
影响因子：
7.7
通讯作者：
Mei, Yide
中科院分区：
文献类型：
--
作者：
Zhao, Kailiang;Yang, Yang;Mei, Yide
肿瘤抑制因子p53在预防癌症中起着重要作用。p53的活性主要由泛素E3连接酶Mdm 2控制，其靶向p53进行蛋白酶体降解。然而，Mdm 2的调节仍然没有很好地理解。在这里，我们表明，MARCH 7，一个环结构域的泛素E3连接酶，物理上与Mdm 2相互作用，是维持Mdm 2的稳定性所必需的。MARCH 7催化Mdm 2的Lys（63）连接的多泛素化，其阻碍Mdm 2的自泛素化和降解，从而导致Mdm 2的稳定化。MARCH 7还促进Mdm 2依赖性多泛素化和p53降解。此外，MARCH 7能够通过p53依赖性机制调节细胞增殖、DNA损伤诱导的凋亡和肿瘤发生。这些发现揭示了Mdm 2调节的新机制，并揭示MARCH 7是Mdm 2-p53通路的重要调节因子。
The tumor suppressor p53 plays a prominent role in the protection against cancer. The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. However, the regulation of Mdm2 remains not well understood. Here, we show that MARCH7, a RING domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. MARCH7 catalyzes Lys(63)-linked polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and degradation, thereby leading to the stabilization of Mdm2. MARCH7 also promotes Mdm2-dependent polyubiquitination and degradation of p53. Furthermore, MARCH7 is able to regulate cell proliferation, DNA damage-induced apoptosis, and tumorigenesis via a p53-dependent mechanism. These findings uncover a novel mechanism for the regulation of Mdm2 and reveal MARCH7 as an important regulator of the Mdm2-p53 pathway.