Mouse double minute 2 homolog–tumor protein p53 protein–protein interaction (MDM2–p53 interaction)

The MDM2–p53 interaction refers to the protein–protein binding between mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase, and the tumor suppressor p53, a transcription factor known as the "guardian of the genome." MDM2 binds the N-terminal transactivation domain of p53 and acts as its major negative regulator by blocking its transcriptional activity, exporting it from the nucleus, and targeting it for ubiquitination and subsequent proteasomal degradation. This interaction forms an autoregulatory feedback loop: p53 stimulates MDM2 expression, and MDM2 keeps p53 levels low under non-stress conditions. In over half of human cancers retaining wild-type p53, MDM2 is often overexpressed or amplified, functionally suppressing p53 and undermining its tumor-suppressive activity. Therapeutic disruption of the MDM2–p53 protein–protein interaction is an actively pursued anticancer strategy, aiming to reactivate p53 and induce apoptosis or senescence in tumor cells. Several small-molecule MDM2 inhibitors are in clinical development, although resistance and safety remain major challenges.

Other names

MDM2–p53 axisMDM2–p53 complexMDM2–p53 protein–protein interactionMurine double minute 2–p53 interaction

- Inhibition of MDM2–p53 binding: Reactivates wild-type p53 by preventing its degradation and restoring its tumor suppressor functions - p53 activation: Induces cell cycle arrest and apoptosis in tumor cells - Ubiquitination blockade: Prevents MDM2 from marking p53 for proteasomal degradation