A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity

作者：Liang, Lunxi; Wang, Huanbin; Shi, Hubing; Li, Zhaoli; Yao, Han; Bu, Zhigao; Song, Ningning; Li, Chushu; Xiang, Dabin; Zhang, Yao; Wang, Jilin; Hu, Ye; Xu, Qi; Ma, Yanlei; Cheng, Zhongyi; Wang, Yingchao; Zhao, Shuliang; Qian, Jin; Chen, Yingxuan; Fang, Jing-Yuan; Xu, Jie^*

来源：Cell Chemical Biology, 2018, 25(6): 761-+.

DOI：10.1016/j.chembiol.2018.03.010

• MUTANT P53
• IN-VIVO
• TUMOR SUPPRESSION
• DEGRADATION
• PROTEIN
• MDM2
• INDUCTION
• DELIVERY
• CELLS
• ACETYLATION

Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53. The molecular functions of Morn3 were validated through in vivo assays and chemico-biological intervention. A rationally designed Morn3-targeting peptide (Morncide) successfully activated p53 and suppressed tumor growth. These findings shed light on the regulation of protein PTMs and present a strategy for targeting two modifications with one molecule.

• 出版日期2018-6-21
• 单位中国农业科学院; 生物治疗国家重点实验室; 兽医生物技术国家重点实验室; 中国农业科学院哈尔滨兽医研究所; 复旦大学; 上海交通大学