Cellular tumor antigen p53-Mouse double minute 4 homolog protein-protein interaction (p53-MDM4 PPI)

The Cellular tumor antigen p53-Mouse double minute 4 homolog (p53-MDM4) protein-protein interaction is a critical regulatory node in the p53 tumor suppressor pathway [3, 9]. MDM4 (also known as MDMX) acts as a potent negative regulator of p53 by binding to its N-terminal transactivation domain, which prevents p53 from interacting with the transcriptional machinery and activating genes involved in cell cycle control and apoptosis [2, 8]. Although MDM4 lacks intrinsic E3 ubiquitin ligase activity, it forms heterodimers with its homolog MDM2 to significantly enhance the ubiquitination and proteasomal degradation of p53 [1, 12]. Overexpression of MDM4 is a frequent occurrence in various human cancers, such as melanoma, breast cancer, and retinoblastoma, where it serves to functionally inactivate p53 even in the absence of TP53 mutations [5, 21]. Therapeutic strategies targeting this interaction, particularly through dual MDM2/MDM4 inhibitors like ALRN-6924, aim to restore p53 activity to induce tumor cell death and overcome resistance associated with selective MDM2 inhibition [6, 18]. Clinical development of these inhibitors focuses on patients with wild-type TP53 status, using biomarkers like GDF15 to monitor p53 reactivation [10, 18].

Other names

p53-MDMX interactionp53-HDM4 interactionMDM4-p53 protein-protein interactionMDMX-p53 interactionp53-MDM4 interaction

Inhibition of the protein-protein interaction between the p53 transactivation domain and the N-terminal hydrophobic pocket of MDM4 to prevent the masking of p53 transcriptional activity and its degradation via MDM2-MDM4 heterodimers, thereby restoring p53-mediated tumor suppression [2, 12, 15].