突变体p53的翻译后修饰与“功能获得”

The Posttranslational Modifications in Regulating the Gain-of-function of the Mutant p53

p53是细胞内最重要的抑癌基因之一,超过50%的人类肿瘤存在以错义突变为主的p53基因变异,导致肿瘤细胞中突变体p53蛋白的产生和积累。除了丧失正常的生物学功能、并通过显性负效应抑制野生型p53的转录活性和肿瘤抑制能力,越来越多的研究表明,突变体p53的“功能获得(gain-of-function)”是其促进肿瘤进展和转移的重要途径。翻译后修饰是调节p53分子功能的关键方式,对野生型p53及不同类型突变体p53的调控表现出普遍性和特异性的双重特征,是靶向突变体p53进而逆转肿瘤的新兴潜在靶点。本文以突变体p53的翻译后修饰为切入点,对突变体p53通过“功能获得”参与肿瘤发生发展的过程、翻译后修饰对突变体p53的调控机制,以及靶向突变体p53及其翻译后修饰在肿瘤治疗中的应用做一综述。此外,我们还讨论了突变体p53在肿瘤生物学研究中尚未解决的问题,并对未来的研究方向进行了展望。本综述旨在系统概括翻译后修饰对突变体p53“功能获得”的调控和在肿瘤发生发展中的意义,为开发基于靶向突变体p53翻译后修饰的肿瘤干预策略提供依据。

p53 is one of the most crucial tumor suppressor genes in mammalian cells.Over 50%of human tumors exhibit p 53 mutations,predominantly consisting of the missense mutations,leading to the generation and accumulation of mutant p53 protein in tumor cells.Apart from losing its normal biological functions and inhibiting the transactivity and tumor suppressive action of wildtype p53 through dominant negative effect,accumulating evidences indicate that the“gain-of-function”of mutant p53 plays critical roles in promoting tumor progression and metastasis.The posttranslational modifications(PTMs)represent a key mechanism by which the molecular functions of both the wildtype p53 and a spectrum of various mutant p53 can be regulated through universal or mutant p53-specific ways.Thus,the PTMs may represent an emerging potential target for reversing mutant p53-driven tumors.Here by focusing on the PTMs of mutant p53,the review provides an overview of how mutant p53 participates in the process of tumor initiation and progression through“gain-of-function”,the regulatory mechanisms of PTMs on mutant p53,and the applications of targeting mutant p53 and its PTMs in cancer treatment.Additionally,we discuss unresolved issues regarding the roles of mutant p53 in cancer biology and provide insights into future research direction.This review comprehensively summarizes the regulatory networks of mutant p53“gain-of-function”by PTMs in tumor development,serving as a basis for developing intervention strategies by targeting the PTMs of mutant p53 in cancer.