Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2
Abstract
The glucocorticoid receptor (GR) and the tumor supressor 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 p21WAF1/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.
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Footnotes
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↵1 Present address: Laboratory of Human Carcinogenesis, Building 37, Room 2C23, 37 Convent Drive, National Cancer Institute, NIH Bethesda, MD 20892, USA.
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↵2 Corresponding author.
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E-MAIL boh{at}igbmc.u-strasbg.fr; FAX 33-3-88-65-32-01.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.202201.
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- Received March 5, 2001.
- Accepted July 26, 2001.
- Cold Spring Harbor Laboratory Press
