REGγ deficiency promotes premature aging via the casein kinase 1 pathway.

TitleREGγ deficiency promotes premature aging via the casein kinase 1 pathway.
Publication TypeJournal Article
Year of Publication2013
AuthorsLi, L, Zhao, D, Wei, H, Yao, L, Dang, Y, Amjad, A, Xu, J, Liu, J, Guo, L, Li, D, Li, Z, Zuo, D, Zhang, Y, Liu, J, Huang, S, Jia, C, Wang, L, Wang, Y, Xie, Y, Luo, J, Zhang, B, Luo, H, Donehower, LA, Moses, RE, Xiao, J, O'Malley, BW, Li, X
JournalProc Natl Acad Sci U S A
Volume110
Issue27
Pagination11005-10
Date Published2013 Jul 2
ISSN1091-6490
KeywordsAging, Premature, Animals, Autoantigens, Casein Kinase Idelta, Female, Genes, p53, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Skin, Tumor Suppressor Protein p53
Abstract

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.

DOI10.1073/pnas.1308497110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23766372
PubMed Central IDPMC3703992
Grant List1R01CA131914 / CA / NCI NIH HHS / United States
92214-1 / / Canadian Institutes of Health Research / Canada
HD08818 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
P30-DK079638 / DK / NIDDK NIH HHS / United States