Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2.
The glucocorticoid receptor (GR) and the tumor suppressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates 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). Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubiquitylation of GR and p53. The ubiquitylation of GR requires p53, the interaction of p53 with Hdm2, and E3 ligase activity of Hdm2. These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival.
Sengupta
S
S
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch cedex, France.
Wasylyk
B
B
D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D016685:Mitomycin / Q000494:pharmacology; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D008024:Ligands; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D003907:Dexamethasone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2