E3 ubiquitin-protein ligase Mdm2 (MDM2) (MDM2)

E3 ubiquitin-protein ligase Mdm2 (MDM2) is a critical negative regulator of the p53 tumor suppressor protein [1][2]. It functions by binding to the N-terminal transactivation domain of p53, which blocks p53-mediated transcriptional activation and facilitates the export of p53 from the nucleus [3]. Most importantly, MDM2 acts as an E3 ubiquitin ligase that targets p53 for proteasomal degradation, maintaining low p53 levels under normal cellular conditions [1][4]. In many human cancers, MDM2 is overexpressed or amplified, leading to the functional inactivation of wild-type p53 and driving oncogenesis [5]. Therapeutic strategies focus on small-molecule inhibitors that occupy the p53-binding pocket of MDM2, thereby stabilizing p53 and restoring its ability to induce cell cycle arrest and apoptosis in malignant cells [4][6]. These inhibitors are primarily being evaluated in patients with TP53 wild-type tumors or MDM2-amplified liposarcomas, though hematologic toxicities like thrombocytopenia remain a significant clinical challenge [5][6]. Sources: [1] UniProt (P22301): https://www.uniprot.org/uniprotkb/P22301/entry [2] NCBI Gene (4193): https://www.ncbi.nlm.nih.gov/gene/4193 [3] Wade, M., Li, Y. C., & Wahl, G. M. (2013). MDM2, MDMX and p53 in cancer: mastering the intricacies of a complex relationships. Nature Reviews Cancer, 13(2), 83-96. [4] Burgess, A., et al. (2016). Clinical Overview of MDM2/X-p53 Interactions in Cancer: Beyond Nutlins. Frontiers in Oncology. [5] Konopleva, M., et al. (2020). MDM2 inhibition: An important step forward in cancer therapy. Nature Reviews Clinical Oncology. [6] ClinicalTrials.gov: MDM2 inhibitor search results.

Other names

Hdm2Double minute 2 proteinp53-binding protein Mdm2Oncoprotein MDM2MDM2 proto-oncogene

Small molecule inhibition of the MDM2-p53 protein-protein interaction, which prevents the ubiquitination and degradation of p53, thereby restoring p53-mediated tumor suppression [3][5].