Forkhead box O4–tumor protein p53 protein–protein interaction (FOXO4–p53 interaction)

The FOXO4–p53 protein–protein interaction refers to the binding between the transcription factor Forkhead box O4 (FOXO4) and the tumor suppressor protein p53. Under cellular stress, the interaction occurs mainly via the transactivation domain (TAD), particularly TAD2, of p53 and the N-terminal Forkhead (FH) DNA-binding domain of FOXO4[1][2][3][4][5][6][7]. This interaction leads to sequestration of p53 in the nucleus, induction of p21-driven cell cycle arrest, and promotion of cellular senescence. The FOXO4–p53 complex is structurally heterogeneous and its formation blocks p53 binding to DNA, but does not affect FOXO4’s DNA-binding capability[3][4]. Disrupting the interaction is being explored as a therapeutic strategy against age-related diseases and cancer by facilitating the clearance of senescent cells[3][7]. No approved drugs currently exist, but preclinical research has shown that interfering peptides can selectively induce apoptosis in senescent cells by disrupting FOXO4–p53 binding[3][7].

Other names

FOXO4–p53 axisFOXO4–p53 complexFOXO4-p53 bindingFOXO4 Forkhead domain–p53 transactivation domain interaction

Inhibition of FOXO4–p53 interaction disrupts sequestration of p53 in senescent cells, restores p53-driven apoptosis, and enables clearance of senescent cells[3]. - Inhibitors can block FOXO4–p53 complex formation, thereby reactivating p53 pathway in targeted cells.