title: REGγ deficiency promotes premature aging via the casein kinase 1 pathway.
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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Dengpan
authors.initials: D
authors.lastname: Zhao
authors.forename: Haibin
authors.initials: H
authors.lastname: Wei
authors.forename: Liangfang
authors.initials: L
authors.lastname: Yao
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Dang
authors.forename: Ali
authors.initials: A
authors.lastname: Amjad
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Linjie
authors.initials: L
authors.lastname: Guo
authors.forename: Dongqing
authors.initials: D
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Zuo
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.forename: Caifeng
authors.initials: C
authors.lastname: Jia
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Xie
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Bianhong
authors.initials: B
authors.lastname: Zhang
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Robb E
authors.initials: RE
authors.lastname: Moses
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D019588:Aging, Premature / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D048148:Casein Kinase Idelta / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency* / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D048148:Casein Kinase Idelta; D046988:Proteasome Endopeptidase Complex
keywords: PA28γ; casein kinase 1