S. Sengupta et B. Wasylyk, Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2, GENE DEV, 15(18), 2001, pp. 2367-2380
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.