PMID:15870285

Citation	Ki, SH, Cho, IJ, Choi, DW and Kim, SG (2005) Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Mol. Cell. Biol. 25:4150-65
Abstract	The expression of the glutathione S-transferase gene (GST), whose induction accounts for cancer chemoprevention, is regulated by activation of CCAAT/enhancer binding protein beta (C/EBPbeta) and NF-E2-related factor 2 (Nrf2). The present study investigated the repressing effects of activating glucocorticoid receptor (GR) on C/EBPbeta- and Nrf2-mediated GSTA2 gene induction and the mechanism. Dexamethasone that activates GR inhibited constitutive and oltipraz- or tert-butylhydroquinone (t-BHQ)-inducible GSTA2 expression in H4IIE cells. Also, dexamethasone repressed GSTA2 promoter-luciferase gene activity. Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPbeta or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ. Deletion of the glucocorticoid response element (GRE) in the GSTA2 promoter abolished dexamethasone inhibition of the gene induction. Immunoprecipitation-immunoblotting, chromatin immunoprecipitation, and GST pull-down assays revealed that silencing mediator for retinoid and thyroid hormone receptors (SMRT), a corepressor recruited to steroid-GR complex for histone deacetylation, bound to TAD domain of C/EBPbeta and Neh4/5 domain of Nrf2. The GSTA2 promoter-luciferase activities were decreased by SMRT but not by truncated SMRTs. The small interference RNA (siRNA) against SMRT abolished SMRT repression of the gene induction by C/EBPbeta or Nrf2. The plasmid transfection and siRNA experiments directly evidenced the functional role of SMRT in GSTA2 repression. In conclusion, dexamethasone antagonizes C/EBPbeta- and Nrf2-mediated GSTA2 gene induction via ligand-GR binding to the GRE, and steroid-mediated GSTA2 repression involves inactivation of C/EBPbeta and Nrf2 by SMRT recruited to steroid-GR complex.
Links	PubMed PMC1087722 Online version:10.1128/MCB.25.10.4150-4165.2005
Keywords	Acetylation/drug effects; Animals; Binding Sites; CCAAT-Enhancer-Binding Protein-beta/chemistry; CCAAT-Enhancer-Binding Protein-beta/genetics; CCAAT-Enhancer-Binding Protein-beta/metabolism; Cell Line; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dexamethasone/pharmacology; Down-Regulation; Glutathione Transferase/genetics; Histones/metabolism; Isoenzymes/genetics; Mice; NF-E2-Related Factor 2; Nuclear Receptor Co-Repressor 2; Promoter Regions, Genetic/genetics; Protein Binding; Rats; Receptors, Glucocorticoid/metabolism; Repressor Proteins/metabolism; Response Elements/genetics; Trans-Activators/chemistry; Trans-Activators/genetics; Trans-Activators/metabolism
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