p21WAF1/CIP1 promotes p53 protein degradation by facilitating p53-Wip1 and p53-Mdm2 interaction

被引:14
作者
Lee, Jihyun [1 ]
Kim, Jongdoo [1 ,2 ]
Kim, Eun Mi [1 ,3 ]
Kim, Ukjin [1 ]
Kang, A-Ram [1 ]
Park, Jong Kuk [1 ]
Um, Hong-Duck [1 ]
机构
[1] Korea Inst Radiol & Med Sci, Div Radiat Biomed Res, Nowon Ro 75, Seoul 01812, South Korea
[2] Seoul Natl Univ, Korea Mouse Phenotyping Ctr, Seoul, South Korea
[3] Seoul Natl Univ, Res Inst Pharmaceut Sci, Seoul, South Korea
基金
新加坡国家研究基金会;
关键词
p53; p21; Wip1; Mdm2; Tumor suppression;
D O I
10.1016/j.bbrc.2021.01.074
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
Downregulation of the p53 tumor suppressor in cancers is frequently accompanied by the upregulation of Wip1 (a phosphatase) and Mdm2 (an E3 ubiquitin ligase). Mdm2 binds and ubiquitinates p53, pro-moting its degradation by the proteasome. As the p53/Mdm2 interaction is alleviated by the phosphorylation of the serine-15 (S15) residue of p53, Wip1, which can directly dephosphorylate phospho-S15, facilitates the Mdm2-mediated degradation of p53. Here, we found that p21(WAF1/CIP1), previously shown to bind p53 and Mdm2, reduces the cellular levels of p53 protein by decreasing its stability. This is accompanied by a decrease in p53-S15 phosphorylation levels. In agreement, p21 promotes the p53/Wip1 interaction. Additionally, p21 interacts with Wip1, forming a trimeric complex of p53, p21, and Wip1. Studies using a p21 deletion mutant that cannot bind p53 revealed that the p53/p21 complex is more efficient than p53 alone in facilitating the binding of p53 to Wip1 and Mdm2. These findings indicate that p21 is a novel negative regulator of p53 stability and therefore, may be used as a target to restore p53 activity by preventing the action of Wip1 and Mdm2 on p53. (C) 2021 The Authors. Published by Elsevier Inc.
引用
收藏
页码:23 / 28
页数:6
相关论文
共 23 条
[1]   p21 in cancer: intricate networks and multiple activities [J].
Abbas, Tarek ;
Dutta, Anindya .
NATURE REVIEWS CANCER, 2009, 9 (06) :400-414
[2]  
Broude EV, 2007, CELL CYCLE, V6, P1468
[3]   Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity [J].
Giannakakou, P ;
Robey, R ;
Fojo, T ;
Blagosklonny, MV .
ONCOGENE, 2001, 20 (29) :3806-3813
[4]  
HOLLSTEIN M, 1994, NUCLEIC ACIDS RES, V22, P3551
[5]   MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation [J].
Jin, YT ;
Lee, HJ ;
Zeng, SLX ;
Dai, MS ;
Lu, H .
EMBO JOURNAL, 2003, 22 (23) :6365-6377
[6]   Structure-function-rescue: the diverse nature of common p53 cancer mutants [J].
Joerger, A. C. ;
Fersht, A. R. .
ONCOGENE, 2007, 26 (15) :2226-2242
[7]   AMP-activated protein kinase induces a p53-dependent metabolic checkpoint [J].
Jones, RG ;
Plas, DR ;
Kubek, S ;
Buzzai, M ;
Mu, J ;
Xu, Y ;
Birnbaum, MJ ;
Thompson, CB .
MOLECULAR CELL, 2005, 18 (03) :283-293
[8]   Bcl-2 Protein Targeting by the p53/p21 Complex-Response [J].
Kim, Eun Mi ;
Kim, Jongdoo ;
Um, Hong-Duck .
CANCER RESEARCH, 2018, 78 (10) :2772-2774
[9]   The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins [J].
Kim, Eun Mi ;
Jung, Chan-Hun ;
Kim, Jongdoo ;
Hwang, Sang-Gu ;
Park, Jong Kuk ;
Um, Hong-Duck .
CANCER RESEARCH, 2017, 77 (11) :3092-3100
[10]   Bcl-w promotes cell invasion by blocking the invasion-suppressing action of Bax [J].
Kim, Eun Mi ;
Kim, Jongdoo ;
Park, Jong Kuk ;
Hwang, Sang-Gu ;
Kim, Wun-Jae ;
Lee, Won-Jae ;
Kang, Sang Won ;
Um, Hong-Duck .
CELLULAR SIGNALLING, 2012, 24 (06) :1163-1172