Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2

The glucocorticoid receptor (GR) and the tumor supressor p53 mediate differ ent stress responses. We have studied the mechanism of their mutual inhibit ion in normal endothelial cells (HUVEC) in response to hypoxia, a physiolog ical stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimul ates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia. Dex inhibits the functions of p53 (apoptosis, Bax, and p21(WAF1/CIP1) expression) and GR (PEPCK and G-6-Pase expression). Endo genous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubi quitylation of GR and p53. The ubiquitylation of GR requires p53, the inter action of p53 with Hdm2, and E3 ligase activity of Hdm2. These results prov ide a mechanistic basis for GR and p53 acting as opposing forces in the dec ision between cell death and survival.