癌症中p53失活的分子机制和靶向p53的抗癌药物研究进展

Research Progress on Molecular Mechanism of p53 Inactivation in Cancers and Drugs Targeting p53

肿瘤抑制因子p53主要作为转录因子发挥作用。当细胞受到诸如缺氧、DNA损伤等胁迫时,p53蛋白迅速在细胞内积聚并激活,从而调控一系列基因的转录,导致细胞周期停顿、凋亡或衰老,避免细胞癌化。p53功能的失活往往导致癌症发生。编码p53蛋白的TP53基因的突变是p53失活的主要方式。突变型p53不仅失去抑癌作用,而且还具有显性负效应,并获得致癌的新功能。其次,野生型p53的功能还受到相互作用蛋白质或非编码RNA的调控,p53正调控因子的下调或/和负调控因子的上调可以导致野生型p53蛋白功能的失活。p53是一个重要的癌症药物靶点,许多研究证实可通过恢复突变型p53的正常功能、降解突变型p53蛋白或者增强野生型p53蛋白的稳定性和活性,达到治疗癌症的目标。本文在对癌症数据库和蛋白质相互作用数据库进行挖掘分析的基础上,综述了TP53基因的突变、p53相互作用蛋白和非编码RNA对p53功能的影响,并介绍了靶向p53的抗癌药物开发现状,可为p53研究和靶向p53的抗癌药物的开发提供参考。

The tumor suppressor p53 functions mainly as a transcription factor.It accumulates in cells and becomes activated in response to various cellular stresses such as hypoxia or DNA damage.Upon activation,p53 regulates the transcription of a series of genes,resulting in cell cycle arrest,apoptosis or senescence to prevent tumorigenesis.Dysfunction of p53 often leads to cancer.Mutation of the TP53 gene that encodes p53 protein is the main way of inactivating p53.Mutant p53 not only loses the tumor suppressive activity,but also gains dominant negative effect and new oncogenic property.Additionally,the function of wild-type p53 is regulated by its interacting proteins or non-coding RNA.Down-regulation of its positive regulators or/and up-regulation of its negative regulators can also inactivate wild-type p53.p53 is an important drug target.Many studies have demonstrated that cancer can be treated through restoring the normal function of mutant p53,degrading it,or enhancing the stability and activity of the wild-type protein.Based on the analysis of public cancer database and protein-protein interaction database,the influences of TP53 mutation,p53-interacting partners and non-coding RNA on p53 function are summarized,and the current status of the development of p53-targeted drugs is also introduced,which may be helpful for p53 and related drug research.