Double minute 4 protein (MDM4) (MDM4)

Double minute 4 protein (MDM4), also known as MDMX, is a key negative regulator of the tumor suppressor p53. MDM4 binds directly to the p53 transcriptional activation domain via its N-terminus, inhibiting p53's ability to mediate cell cycle arrest and apoptosis[2][3]. Unlike MDM2, which also binds p53 but possesses intrinsic E3 ubiquitin ligase activity for p53 degradation, MDM4 primarily suppresses p53 transcriptional activity and cooperates with MDM2 to facilitate p53 degradation through protein–protein interactions[4][5]. MDM4 is fine-tuned by post-translational modifications—including several key phosphorylation events—that regulate its function in response to cellular stress and DNA damage[2]. MDM4 is frequently overexpressed or amplified in human cancers, conferring resistance to DNA-damaging chemotherapy and inhibiting p53-dependent apoptosis[1]. MDM4 can localize to the mitochondria where it further modulates p53-dependent intrinsic apoptotic pathways, acting as an anchor for the proapoptotic phosphorylated form of p53 and facilitating cytochrome C release[1]. Therapeutic strategies targeting MDM4 are in development, aiming to reactivate p53 tumor suppressor function in malignancies with wild-type p53.

Other names

MDMXHDMXp53-binding protein Mdm4Mdm2-like p53-binding proteinProtein MdmxBMFS6MRP1Double minute 4 proteinHuman homolog of p53-binding protein

Inhibition of MDM4–p53 interaction restores p53 tumor suppressor function, driving cell cycle arrest or apoptosis in cancer cells. Dual inhibition of MDM2 and MDM4 can stabilize p53, increasing apoptosis in tumors with wild-type p53.