Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase
Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase
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Siva1 通过充当 ARF E3 泛素连接酶抑制 p53 功能
DOI：
10.1038/ncomms2533
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发表时间：
2013-03-01
影响因子：
16.6
通讯作者：
Wu, Mian
中科院分区：
文献类型：
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作者：
Wang, Xingwu;Zha, Meng;Wu, Mian
肿瘤抑制因子替代阅读框架（ARF）是人类癌症中最常见的突变蛋白之一。已经确定ARF能够通过直接抑制Mdm 2来稳定和激活p53。ARF介导的p53激活对致癌应激的反应被认为是保护免受癌症的重要决定因素。然而，关于细胞中ARF的控制知之甚少。在这里，我们表明，Siva 1是一个特定的E3泛素连接酶的ARF。Siva 1与ARF在体外和体内均存在物理相互作用，通过直接作用促进ARF的泛素化和降解，进而影响p53的稳定性。在功能上，Siva 1以ARF/p53依赖性方式调节细胞周期进程和细胞增殖。我们的研究结果揭示了一种新的调节机制，用于控制ARF的稳定性，从而揭示了Siva 1在调节ARF-Mdm 2-p53通路中的重要功能。
The tumour suppressor alternative reading frame (ARF) is one of the most frequently mutated proteins in human cancer. It has been well established that ARF is able to stabilize and activate p53 by directly inhibiting Mdm2. ARF-mediated p53 activation in response to oncogenic stress is thought to be an important determinant of protection against cancer. However, little is known regarding the control of ARF in cells. Here, we show that Siva1 is a specific E3 ubiquitin ligase of ARF. Siva1 physically interacts with ARF bothin vitroandin vivo.Through direct interaction, Siva1 promotes the ubiquitination and degradation of ARF, which in turn affects the stability of p53. Functionally, Siva1 regulates cell cycle progression and cell proliferation in an ARF/p53-dependent manner. Our results uncover a novel regulatory mechanism for the control of ARF stability, thereby revealing an important function of Siva1 in the regulation of the ARF-Mdm2-p53 pathway.