hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14

被引:52
作者
Zhang, J. [1 ,2 ]
Bai, D. [1 ,2 ]
Ma, X. [2 ]
Guan, J. [1 ,2 ]
Zheng, X. [1 ,2 ]
机构
[1] State Key Lab Prot & Plant Gene Res, Beijing, Peoples R China
[2] Peking Univ, Dept Biochem & Mol Biol, Sch Life Sci, Beijing 100871, Peoples R China
基金
美国国家科学基金会;
关键词
hCINAP; RPS14; NEDDylation; HDM2; p53; ADENYLATE KINASE; P53; HDM2; MDM2; IDENTIFICATION; DEGRADATION; ACTIVATION; FAP7;
D O I
10.1038/onc.2012.560
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The tumor-suppressor p53 provides a critical brake on tumor development. HDM2 (human double-minute 2), a p53 E3 ubiquitin ligase, is the principal cellular antagonist of p53. Mounting evidence has suggested that ribosomal proteins (RPs) modulate HDM2-p53 as a novel pathway for regulating p53 signaling. However, the upstream regulators that mediate RP-HDM2-p53 circuits remain poorly understood. Here we identify human coilin-interacting nuclear ATPase protein (hCINAP) as an interacting partner of ribosomal protein S14 (RPS14). RPS14 stabilized and activated p53 by inhibiting HDM2-mediated p53 polyubiquitination and degradation. More importantly, RPS14 was specifically modified with NEDD8 and hCINAP inhibited RPS14 NEDDylation by recruiting NEDD8-specific protease 1. The decrease in RPS14 NEDDylation led to reduced stability and incorrect localization of RPS14, thereby attenuating the interaction between RPS14 and HDM2. Free HDM2 stimulated p53 polyubiquitination and degradation. In conclusion, we demonstrate that hCINAP acts as a novel regulator of RPS14-HDM2-p53 by regulating the interaction between RPS14 and HDM2 through the control of RPS14 NEDDylation. These findings suggest that hCINAP is an important regulator of RP-HDM2-p53 pathway and a potential anticancer drug target.
引用
收藏
页码:246 / 254
页数:9
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