Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation
Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation
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DOI：
10.1016/s0092-8674(03)00193-4
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发表时间：
2003-03-21
期刊：
影响因子：
64.5
通讯作者：
Benchimol, S
中科院分区：
文献类型：
--
作者：
Leng, RP;Lin, YP;Benchimol, S
p53 肿瘤抑制因子针对各种类型的应激（包括 DNA 损伤和异常增殖信号）发挥抗增殖作用。 p53 的严格调控对于维持正常细胞生长至关重要，这主要通过 p53 的翻译后修饰发生。在这里，我们描述了 Pirh2，这是一种受 p53 调控的基因，编码具有内在泛素蛋白连接酶活性的包含 RING-H2 结构域的蛋白质。 Pirh2 与 p53 发生物理相互作用，并独立于 Mdm2 促进 p53 泛素化。 Pirh2 的表达降低了 p53 蛋白的水平，而内源性 Pirh2 表达的消除则增加了 p53 的水平。此外，Pirh2 抑制 p53 功能，包括 p53 依赖性反式激活和生长抑制。我们认为 Pirh2 通过物理相互作用和泛素介导的蛋白水解参与 p53 功能的负调节。因此，Pirh2 与 Mdm2 一样，参与控制 p53 功能的自动调节反馈循环。
The p53 tumor suppressor exerts anti-proliferative effects in response to various types of stress including DNA damage and abnormal proliferative signals. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through post-translational modifications of p53. Here, we describe Pirh2, a gene regulated by p53 that encodes a RING-H2 domain-containing protein with intrinsic ubiquitin-protein ligase activity. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of Mdm2. Expression of Pirh2 decreases the level of p53 protein and abrogation of endogenous Pirh2 expression increases the level of p53. Furthermore, Pirh2 represses p53 functions including p53-dependent transactivation and growth inhibition. We propose that Pirh2 is involved in the negative regulation of p53 function through physical interaction and ubiquitin-mediated proteolysis. Hence, Pirh2, like Mdm2, participates in an autoregulatory feedback loop that controls p53 function.