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首页> 外文期刊>Cell cycle >CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination.
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CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination.

机译：CSA和CSB蛋白与p53相互作用并调节其Mdm2依赖性泛素化。

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摘要

Mutations in Cockayne syndrome (CS) A and B genes (CSA and CSB) result in a rare genetic disease that affects the development and homeostasis of a wide range of tissues and organs. We previously correlated the degenerative phenotype of patients to the enhanced apoptotic response, exhibited by CS cells, which is associated with the exceptional induction of p53 protein, upon a variety of stress stimuli. Here we showed that the elevated and persistent levels of p53 displayed by CS cells are due to the insufficient ubiquitination of the p53 protein. We further demonstrated that CSA and CSB proteins associate in a unique complex with p53 and Mdm2; this interaction greatly stimulates the ubiquitination of p53 in an Mdm2-dependent manner. Tandem affinity purification and immunoprecipitations combined with mass spectrometry studies indicate that CSA and CSB associate within a Cullin Ring Ubiquitin Ligase complex responsible, under certain circumstances, for p53 ubiquitination. This study identifies CSA and CSB as the key elements of a regulatory mechanism that equilibrate beneficial and detrimental effects of p53 activity upon cellular stress. The deregulation of p53, in absence of either of the CS proteins, can potentially explain the early onset degeneration of tissues and organs observed in CS patients.
机译：Cockayne综合征（CS）A和B基因（CSA和CSB）的突变会导致罕见的遗传病，这种疾病会影响多种组织和器官的发育和体内稳态。我们以前将患者的退化表型与CS细胞表现出的凋亡反应增强相关联，后者在多种应激刺激下与p53蛋白的异常诱导有关。在这里，我们显示CS细胞显示的p53升高和持续水平是由于p53蛋白的泛素化不足所致。我们进一步证明，CSA和CSB蛋白与p53和Mdm2形成独特的复合体。这种相互作用以依赖Mdm2的方式极大地刺激了p53的泛素化。串联亲和纯化和免疫沉淀结合质谱研究表明，CSA和CSB在一个Cullin环泛素连接酶复合物中结合，在某些情况下负责p53泛素化。这项研究确定CSA和CSB是平衡p53活性对细胞应激的有益和有害作用的调节机制的关键要素。在缺少任何一种CS蛋白的情况下，p53的失调都可能解释CS患者中观察到的组织器官早期退化。

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