Mouse double minute 2 homolog-Mouse double minute 4 homolog RING domain heterodimer (MDM2-MDM4 RING heterodimer) (MDM2-MDM4 RING heterodimer)

The Mouse double minute 2 homolog (MDM2)-Mouse double minute 4 homolog (MDM4) RING domain heterodimer is a critical E3 ubiquitin ligase complex that serves as the primary negative regulator of the p53 tumor suppressor protein (Wade et al., 2013, PMID: 23246852). While MDM2 possesses intrinsic catalytic activity for ubiquitination, its efficiency is significantly enhanced through heterodimerization with its homolog MDM4 (also known as MDMX) via their respective C-terminal RING domains (Link et al., 2005, PMID: 16170334). This complex facilitates the polyubiquitination of p53, leading to its subsequent degradation by the 26S proteasome and maintaining p53 at low levels under non-stressed conditions. In many human cancers, such as sarcomas and leukemias, MDM2 and MDM4 are frequently overexpressed or amplified, resulting in the pathological suppression of wild-type p53 and the evasion of apoptosis (Katz et al., 2018, PMID: 29930118). Therapeutic strategies targeting this heterodimer include dual inhibitors like the stapled peptide ALRN-6924, which blocks the p53-binding sites on both MDM2 and MDM4, as well as experimental agents designed to disrupt the RING-RING interface itself (Meric-Bernstam et al., 2023, PMID: 36638311). By inhibiting this complex, drugs aim to stabilize p53 and reactivate its ability to induce cell cycle arrest and apoptosis in malignant cells.

Other names

MDM2-MDMX complexHDM2-HDMX heterodimerMDM2-MDM4 E3 ligase complexRING-RING heterodimerp53-MDM2-MDM4 regulatory complex

Inhibition of the MDM2-MDM4 E3 ligase complex activity or disruption of the p53-binding interface to prevent p53 ubiquitination and degradation, thereby restoring p53-mediated tumor suppression.