Title | REGγ deficiency promotes premature aging via the casein kinase 1 pathway. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Li, 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 |
Journal | Proc Natl Acad Sci U S A |
Volume | 110 |
Issue | 27 |
Pagination | 11005-10 |
Date Published | 2013 Jul 2 |
ISSN | 1091-6490 |
Keywords | Aging, 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. |
DOI | 10.1073/pnas.1308497110 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 23766372 |
PubMed Central ID | PMC3703992 |
Grant List | 1R01CA131914 / 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 |