MDM2s

MDM2s refers to the family of proteins that regulate the tumor suppressor p53, most notably MDM2 and its homolog MDM4 (also known as MDMX). Together, these proteins modulate p53 activity in response to cellular stress by controlling its stability and transcriptional output. The MDM2 gene is a well-studied target of p53, creating a negative feedback loop in which p53 induces MDM2 expression and MDM2 then restrains p53.

MDM2 itself is an E3 ubiquitin ligase that binds the N-terminal transactivation domain of p53, inhibiting p53-dependent transcription. It also promotes ubiquitination and proteasomal degradation of p53, reducing p53 levels and activity. The MDM2 protein contains an N-terminal p53-binding region, a central acidic domain, and a C-terminal RING finger domain responsible for its ligase activity. MDM2 can form homodimers and can also interact with MDM4. Through these interactions, MDM2 can fine-tune p53 regulation across different cell types and conditions.

MDM4/MDMX is a conserved homolog that shares structural similarity with MDM2 but generally lacks strong intrinsic E3 ligase activity. It binds p53 and can suppress p53's transcriptional activity. MDM4 often functions in concert with MDM2, forming heterodimers that enhance the suppression and degradation of p53 in various cellular contexts.

Regulation of MDM2s is influenced by stress signaling pathways such as ATM/CHK and can be modified by phosphorylation and other post-translational changes. In cancer, amplification or overexpression of MDM2 and MDM4 is common and is associated with reduced p53 tumor-suppressor activity. Therapeutic strategies aiming to reactivate p53 frequently target the MDM2–p53 interaction, with several inhibitors in clinical development or available for research use.