REGγ Deficiency Promotes Premature Ageing Via The Ck1δ-Mdm2-p53pathway

REGγ (PA28γ, PSME3, Ki antigen) belongs to a family of activators of the11S proteasome. REGγ is localized in the nucleus and has been implicated in the regulation of cell cycle progression and apoptosis, REGγ has been reported to be associated with some types of cancers and has been recently shown to promote the degradation of several important regulatory proteins, including the cyclin-dependent kinase inhibitor p21,SRC3, p19, HCV core protein and Smurf1. REGγ also has an integral function in the degradation of p53, by acting as an essential cofactor that promotes the binding of Mdm2and p53.This study suggests a role for REGγ in the regulation of p53in vivo and in vitro. Firstly,we found that REGy could downregulate p53protein level in A549cells. However, the molecular details and in vivo biological significance of REGγ-p53interplay remain elusive. Next, we demonstrate that REGγ deficient mice develop premature ageing phenotypes that are associated with abnormal accumulation of p53. Antibody array analysis led us to identify CK18as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of Mdm2. Interestingly, massive increase of p53in REGγ-/-tissues is associated with reduced Mdm2protein levels despite that Mdm2transcription is enhanced. Allelic p53haplodeficiency in REGγ deficient mice significantly attenuated premature ageing features. Furthermore, introducing exogenous Mdm2to REGγ-/-MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53regulatory pathway. Given the dispute over the "anti-ageing" and "pro-ageing" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53regulation in the cellular ageing process. These findings indicate that modulating the activity of the REGγ-proteasome may be an approach for intervening ageing associated disorders.