Reg Gamma Deficiency Promotes Premature Aging Via The Casein Kinase 1 Pathway

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.