The Role Of Hsp90? Interacts With MDM2 To Suppress P53-dependent Senescence During Skeletal Muscle Regeneration

Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration while the underlying mechanisms remain elusive.Recent studies disclosed the emerging roles of heat shock proteins in regulating muscle regeneration.Here we found that Hsp90?,but not Hsp90a isoform,was significantly upregulated during muscle regeneration.RNA-seq analysis disclosed an elevation of p21 transcription in Hsp90?-depleted myoblasts,which is due to the upregulation of p53.Moreover,knockdown of Hsp90? in myoblasts resulted in p53-dependent cellular senescence.In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer,Hsp90? preferentially bound to wildtype p53 and modulated its degradation via a proteasome-dependent manner.Moreover,Hsp90? interacted with MDM2,the chief E3 ligase of p53,to regulate the stability of p53.In line with these in vitro studies,the elevation of p53-p21 axis correlated with the downregulation of Hsp90? in aged mice muscle.Consistently,administration of 17-AAG,a Hsp90 inhibitor under clinical trial,enhanced injury-induced senescence in skeletal muscle and impaired muscle regeneration.Taken together,our finding revealed previously unappreciated roles of Hsp90? in regulating p53 stability to suppress senescence both in vivo and in vitro.