MDM2

MDM2 is a human gene encoding the MDM2 protein, an E3 ubiquitin ligase that acts as a key negative regulator of the tumor suppressor p53. By binding to the N-terminal transactivation domain of p53, MDM2 inhibits p53’s transcriptional activity and promotes ubiquitination of p53, targeting it for proteasomal degradation. This creates a negative feedback loop, because p53 transcriptionally activates MDM2 expression.

Regulation of MDM2 involves multiple partners and pathways. The ARF tumor suppressor (p14ARF in humans) inhibits MDM2, thereby stabilizing p53 in response to oncogenic stress. MDM2 also interacts with MDMX (MDM4), which modulates p53 activity; together they influence p53 signaling. MDM2 is primarily nuclear but can shuttle between the nucleus and cytoplasm, affecting the localization and turnover of p53.

Structure and genetics. MDM2 contains an N-terminal p53-binding domain, a central acidic region, nuclear localization signals, and a C-terminal RING finger domain that mediates its ubiquitin ligase activity. The MDM2 gene is located on chromosome 12q15; amplification or overexpression of MDM2 occurs in several cancers, including liposarcoma and glioblastoma, contributing to reduced p53 function.

Clinical relevance and therapies. In tumors with wild-type p53, inhibitors that disrupt the MDM2–p53 interaction aim to reactivate p53 tumor suppressor activity, with compounds such as Nutlin-3 and its derivatives explored in clinical studies. MDM2 amplification can serve as a biomarker in certain cancers. MDM2 also participates in p53-independent pathways and the cellular DNA damage response, broadening its role in oncogenesis and therapy response.