Tumor protein p73 (TAp73) interaction with MDM2 and MDM4 (TAp73/MDM2/MDM4 PPI)

The TAp73/MDM2 and TAp73/MDM4 protein-protein interactions are pivotal regulatory nodes in the p53 family signaling network. TAp73 is a transcriptionally active isoform of the TP73 gene that functions as a tumor suppressor by inducing apoptosis and cell cycle arrest (UniProt P57050). MDM2 and MDM4 (MDMX) act as the primary negative regulators of TAp73 by binding to its N-terminal transactivation domain, thereby inhibiting its ability to initiate gene transcription (PubMed: 10464299). While MDM2 is an E3 ubiquitin ligase that can target p53 for degradation, its role in TAp73 degradation is more complex and often involves transcriptional interference rather than proteolysis (UniProt P19367). In many human cancers, particularly those harboring TP53 mutations, TAp73 remains wild-type but is functionally silenced by the overexpression of MDM2 or MDM4 (PubMed: 25210018). Therapeutic targeting of these interactions involves the use of small molecules or stapled peptides, such as ALRN-6924, which occupy the MDM2/MDM4 binding pockets and release TAp73 (PubMed: 28899964). This reactivation of TAp73 allows the protein to resume its tumor-suppressive program, providing a strategy to bypass p53 deficiency in malignant cells. Clinical interest in this target is high for treating various solid tumors and hematological malignancies where p53 is lost but p73 is present.

Other names

p73-MDM2 interactionp73-MDMX interactionTAp73-MDM2/MDMX complexp73-MDM2-MDM4 axis

Inhibition of protein-protein interaction (PPI) to prevent MDM2/MDM4-mediated suppression of TAp73, thereby restoring TAp73-dependent apoptosis and cell cycle arrest.