Inhibition of MDM2 by hsp90 Contributes to Mutant p53 Stabilization

摘要: Stabilization and overexpression are hallmarks of mutant p53 found in nearly 50% human tumors. Mutations the conformation-sensitive core domain often lead to association with molecular chaperones such as hsp70 hsp90. Inhibition hsp90 function accelerates degradation. We recently that expression mutants inhibits MDM2 degradation, suggesting can modulate functions. In this report, we show mediates formation MDM2-p53-hsp90 complexes. Release from p53-hsp90 complex after DNA damage restores but not turnover, whereas dissociation by geldanamycin increases degradation both p53. Mutant inhibition requires expression. The interaction between is disrupted 2A10 antibody, which recognizes a site on important for binding alternative reading frame (ARF). Expression prevents ARF accumulating nucleolus an hsp90-dependent fashion. These results suggest recruited conceals ARF-binding its ubiquitin-protein isopeptide ligase function, resulting stabilization MDM2.