Mouse double minute 2 homolog-Tumor protein p53 interface (MDM2-p53)

The Mouse double minute 2 homolog (MDM2)-Tumor protein p53 (p53) protein-protein interface is a critical regulatory node in cell cycle control and tumor suppression [1, 11]. MDM2 acts as the primary negative regulator of p53 by binding to its N-terminal transactivation domain, which inhibits p53-mediated transcription and targets the protein for ubiquitin-dependent proteasomal degradation [1, 12]. In approximately 50% of human cancers, p53 function is lost through mutation; however, in many other cases, p53 remains wild-type but is functionally inactivated by MDM2 overexpression or gene amplification [3, 11]. Therapeutic strategies targeting this interface involve small-molecule inhibitors, often referred to as MDM2 antagonists, which occupy the p53-binding pocket on MDM2 [1, 5]. By disrupting this interaction, these drugs stabilize p53, leading to the reactivation of its downstream pathways, including the induction of cell cycle arrest, senescence, and apoptosis in cancer cells [2, 14]. Clinical trials are primarily focused on patients with TP53 wild-type tumors, such as dedifferentiated liposarcoma and acute myeloid leukemia, though management of hematologic toxicities like thrombocytopenia is a key clinical challenge [5, 9].

Other names

MDM2-p53 interactionMDM2-TP53 complexp53-MDM2 binding siteMDM2-p53 interfaceMDM2-p53 protein-protein interaction

Inhibition of protein-protein interaction, p53 stabilization, and reactivation of p53 tumor suppressor function