TP53 and cancer: Mdm2 is the major E3 ligase of p53, promoting its ubiquitination and proteasomal degradation.8, 9 Mdmx in contrast, inhibits the transcriptional activity of p53 and enhances the ability of Mdm2 to target p53 for degradation, although it does not have an E3 ligase activity of its own.10 Both Mdm2 and Mdmx expression are elevated in various cancer types.