MDM2–p53 protein–protein interaction (MDM2–p53)

The **MDM2–p53 protein–protein interaction** is a central regulatory node in cellular stress response and tumor suppression. MDM2 is an E3 ubiquitin ligase that binds to the N-terminal transactivation domain (TAD) of p53, inhibiting its transcriptional activity, blocking DNA binding, promoting its degradation via ubiquitination, and facilitating nuclear export[1][2][4][5]. This interaction forms a negative feedback loop: p53 transcriptionally upregulates MDM2, which then suppresses p53, maintaining regulated p53 levels under normal conditions. Overexpression or aberrant activation of MDM2—as seen in many cancers—leads to excessive p53 inactivation and enables malignant transformation. Therapeutic disruption of this interaction with small-molecule inhibitors is a major approach in drug development, aiming to release p53-mediated cell cycle arrest and apoptosis selectively in tumor cells[1][5]. Critical interface residues from p53 (Phe19, Trp23, Leu22, Leu26) and MDM2 (Lys51, Leu54, Tyr100, Tyr104) define the specificity of this binding[3][4][5].

Other names

MDM2–p53 interactionMDM2–p53 complexMDM2-p53 bindingMDM2–TP53 interaction

Inhibition of MDM2 binding to p53; Restoration of p53 transcriptional activity; Activation of p53 signaling for cell-cycle arrest and apoptosis in cancer cells.