REGγ deficiency promotes premature aging via the casein kinase 1 pathway

被引：61

作者：

Li, Lei ^{[1
,2
]}

Zhao, Dengpan ^{[1
]}

Wei, Haibin ^{[1
]}

Yao, Liangfang ^{[1
]}

Dang, Yongyan ^{[1
]}

Amjad, Ali ^{[1
]}

Xu, Jinjin ^{[1
]}

Liu, Jiang ^{[1
,3
]}

Guo, Linjie ^{[1
]}

Li, Dongqing ^{[1
]}

Li, Zhen ^{[1
]}

Zuo, Di ^{[1
]}

Zhang, Yuanyuan ^{[1
]}

Liu, Jian ^{[1
,4
]}

Huang, Shixia ^{[4
]}

Jia, Caifeng ^{[1
]}

Wang, Lu ^{[1
]}

Wang, Ying ^{[1
,3
]}

Xie, Yifan ^{[1
]}

Luo, Jian ^{[1
]}

Zhang, Bianhong ^{[1
]}

Luo, Honglin ^{[5
]}

Donehower, Lawrence A. ^{[4
]}

Moses, Robb E. ^{[4
]}

Xiao, Jianru ^{[2
]}

O'Malley, Bert W. ^{[4
]}

Li, Xiaotao ^{[1
,4
]}

机构：

[1] E China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China

[2] Second Mil Med Univ, Dept Orthopaed Oncol, Changzheng Hosp, Shanghai 200003, Peoples R China

[3] Hangzhou Normal Univ, Inst Aging Res, Sch Med, Hangzhou 310036, Zhejiang, Peoples R China

[4] Baylor Coll Med, Dept Mol Mol & Cellular Biol, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[5] Univ British Columbia, James Hogg Res Ctr Cardiovasc & Pulm Res, St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 27期

基金：

美国国家卫生研究院; 加拿大健康研究院; 中国国家自然科学基金;

关键词：

casein kinase 1; PA28; gamma; GROWTH-RETARDATION; P53; ACTIVITY; HUMAN-CELLS; MICE; SENESCENCE; PHOSPHORYLATION; DEGRADATION; PHENOTYPES; TURNOVER; DISTINCT;

D O I：

10.1073/pnas.1308497110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator). in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REG gamma-p53 interplay remain elusive. Here, we demonstrate that REG gamma-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1 delta and p53. Antibody array analysis led us to identify CK1 delta as a direct target of REG gamma. Silencing CK1 delta or inhibition of CK1 delta activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REG gamma(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REG gamma-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REG gamma(-/-) MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REG gamma-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1 delta-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REG gamma-proteasome may be an approach for intervention in aging-associated disorders.

引用

页码：11005 / 11010

页数：6

共 42 条

[1] Immune defects in 28-kDa proteasome activator γ-deficient mice [J].