《生命科学》 2020, 32(5): 446-452

MDM2/MDMX异二聚体及MDMX磷酸化调控p53的研究进展

王　兵1，2，3，王菊芳1*

(1 中国科学院近代物理研究所，甘肃省空间辐射生物学重点实验室，中国科学院重离子辐射
    生物医学重点实验室，兰州 730000；2 中国科学院大学，北京100049；3 John B. Little Center for Radiation Sciences， Harvard T.H. Chan School of Public Health， Boston， MA 02115)

摘　要：

摘　要：p53 作为肿瘤抑制因子在维持机体内稳态和抑制肿瘤发生发展中起到关键作用。超过半数的人类肿瘤中都存在p53 的突变。突变的p53 具有“获得性功能”，反而促进肿瘤的发生、转移和耐药。MDM2和MDMX 是两个最主要的p53 负调控蛋白，二者是同源蛋白，可以独自或以异二聚体的方式调控p53。在多种刺激信号下，MDM2/MDMX 异二聚体对p53 的负调控作用被抑制，使得p53 活化进而激活下游复杂的信号网络，维持细胞内稳态。磷酸化修饰是MDMX 调节的重要方式之一，对其自身的稳定性、核定位以及与MDM2、p53 的相互作用均有影响。该文对以上内容进行简要综述，并对现有治疗靶标和小分子化合物进行讨论，为进一步开发新的有效的肿瘤治疗策略提供思路。

Advances in regulation of p53 by MDM2/MDMX heterodimer and MDMX phosphorylation

WANG Bing1，2，3， WANG Ju-Fang1*

(1 Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Space Radiobiology of Gansu Province and Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences， Institute of Modern Physics， Chinese Academy of Sciences， Lanzhou 730000， China; 2 University of Chinese Academy of Sciences， Beijing 100049， China; 3 John B. Little Center for Radiation Sciences， Harvard T.H. Chan School of Public Health， Boston， MA 02115， USA)

Abstract:

Abstract: The tumor suppressor p53 plays a critical role in guiding homeostasis and restraining the initiation or progression of cancer. Many human tumors carry p53 mutations with novel phenotypes which have contributed to tumor progression， metastasis and increased drug resistance， and these forms are referred to as mutant p53 gain-offunction. The two major essential negative regulators of p53 are MDM2 and MDMX. These homolog proteins work in co-ordination or individually which dictates the turnover of p53 upon diverse cell stress signal. And activated p53 assist in maintaining the cellular homeostasis through transactivating multiple target genes. Studies have shown that phosphorylation of MDMX can affect its degradation， intracellular localization and interaction with MDM2 and p53 and thus regulate p53. This review concentrates on the role of phosphorylation of MDMX and the interaction with MDM2 in regulation of p53. In addition， the review discusses the current anti-tumor therapeutic targets and small molecules， along with the potential and effective therapeutic targets to restore p53 activity.