Mouse double minute 4 homolog (MDM4) (MDM4)

Mouse double minute 4 homolog (MDM4), also known as MDMX, is a critical negative regulator of the p53 tumor suppressor protein (UniProt P49759). It contains an N-terminal p53-binding domain and a C-terminal RING domain, the latter of which is essential for heterodimerization with its homolog MDM2 (PMID: 28841415). While MDM4 lacks intrinsic E3 ubiquitin ligase activity, its interaction with MDM2 via the RING domain is necessary for the efficient polyubiquitination and subsequent proteasomal degradation of p53 (PMID: 25236395). MDM4 is frequently overexpressed or amplified in various human malignancies, such as melanoma and breast cancer, where it effectively silences the p53 pathway even in the absence of TP53 mutations. Therapeutic targeting of MDM4, particularly through the disruption of its RING domain-mediated dimerization or its direct binding to p53 using dual inhibitors like ALRN-6924, aims to reactivate p53-dependent apoptosis and growth arrest in cancer cells (PMID: 29038297).

Other names

MDMXHDMXMdm2-like p53-binding proteinProtein Mdm4Double minute 4 protein

Inhibition of the MDM4-p53 interaction or disruption of the MDM2-MDM4 RING-RING heterodimerization to restore p53 tumor suppressor activity.