The strong effect of CDKIs on p53 activity in cancers overexpressing MDM4 could, depending on the MDM2 and MDM4 protein ratios, simultaneously reflect the following mechanisms: (1) the disruption of MDM4-mediated inhibition of p53 transcriptional activity, (2) the change in the abundance of MDM2/MDM4 heterodimers vs. MDM2/MDM2 homodimers, and (3) the enhanced inhibition of MDM2 activity by ribosomal proteins in the absence of MDM4. This evidence concerns the gene TP53 and cancer.