Cdk5 associates with p53 to phosphorylate at Ser20 and Ser46. (A) HTet26p53 and HTet43GFP cells 12 h pretreated with Cdk2/5 inhibitor were treated with Dox in the presence or absence of OA for 48 h and processed for western blotting with p53, pSer20 and pSer46 antibodies. (B) HTet26p53 and HTet43GFP cells treated as mentioned in (A) were processed for immunoprecipitation with p53 antibody. p53 and Cdk5 immunoblot was done. (C) Model for Cdk5-mediated p53 phosphorylation and activation. Cdk5 phosphorylates p53 which is dephosphorylated by PP2A. Inhibition of PP2A promotes phosphorylation of p53 at Ser20 and Ser46. Activated p53 is recruited on p21 and Bax promoter to execute cell cycle arrest and apoptosis. Cdk5 phosphorylation is not dependent on ERK activation but on an unknown kinase(s).