Article (Scientific journals)
REGγ deficiency promotes premature aging via the casein kinase 1 pathway
Li, Lei; Zhao, Dengpan; Wei, Haibin et al.
2013In Proceedings of the National Academy of Sciences of the United States of America
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Abstract :
[en] Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ−/− tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ−/− MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the “antiaging” and “proaging” effects of p53, our results indicate a key role for CK1δ-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 REGγ-proteasome may be an approach for intervention in aging-associated disorders.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Li, Lei
Zhao, Dengpan
Wei, Haibin
Yao, Liangfang
Dang, Yongyan
Ali, Amjad ;  Université de Liège > Département de pharmacie > Chimie médicale
Xu, Jinjin
Liu, Jiang
Guo, Linjie
Li, Dongqing
Li, Zhen
Di Zuo
Zhang, Yuanyuan
Liu, Jian
Huang, Shixia
Jia, Caifeng
Wang, Lu
Wang, Ying
Xie, Yifan
Luo, Jian
Zhang, Bianhong
Luo, Honglin
Donehower, Lawrence A.
Moses, Robb E.
Xiao, Jianru
O’Malley, Bert W.
Li, Xiaotao
More authors (17 more) Less
Language :
English
Title :
REGγ deficiency promotes premature aging via the casein kinase 1 pathway
Publication date :
07 May 2013
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington, United States - District of Columbia
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 01 June 2015

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