Mouse double minute 2 homolog (MDM2), also known as E3 ubiquitin-protein ligase Mdm2[6] (MDM2 (also HDM2 for human MDM2)[4])

Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that serves as the primary negative regulator of the tumor suppressor protein p53.[1][2] MDM2 controls p53 activity, stability, and nuclear localization through direct binding to p53's N-terminal domain and subsequent ubiquitination, leading to p53 degradation via the proteasome.[1][2] In response to DNA damage, kinases such as ATM phosphorylate MDM2, disrupting its interaction with p53 and allowing p53 stabilization and activation to promote apoptosis or cell cycle arrest.[2] Beyond its p53-dependent functions, MDM2 regulates numerous cellular processes including DNA repair, cell cycle progression, apoptosis, and intracellular trafficking through interactions with multiple protein partners.[1] MDM2 is widely recognized as an oncogenic driver in cancer, with MDM2 amplification or overexpression occurring in numerous tumor types where it inactivates p53's protective functions, promoting cell survival, proliferation, and therapeutic resistance.[2][5] Additionally, MDM2 plays roles in cardiovascular homeostasis through regulation of angiogenesis, atherosclerosis prevention, and cardiac remodeling via both p53-dependent and independent mechanisms.[1] Due to its central role in cancer development, MDM2 has been designated as a therapeutic target of choice, with numerous MDM2 antagonists in active development to disrupt the MDM2-p53 interaction and restore p53 function in cancer cells.[1]

Other names

Murine double minute 2[1]E3 ubiquitin-protein ligase Mdm2[6]Hdm2 (human homolog)[9]Oncoprotein Mdm2[6]p53-binding protein Mdm2[12]

Direct binding to p53 N-terminal transactivation domain, blocking its transcriptional activity[6]; Ubiquitination of p53 leading to proteasomal degradation[1][2]; Regulation of p53 nuclear localization and export[2]; Interaction with DNA repair proteins to inhibit repair processes[2]; Modulation of HIF1-α stability and transcriptional activity[1]; Regulation of E2F1 transcriptional activity[1]; Recycling and desensitization of G protein-coupled receptors including β-adrenergic receptors[1]