Glucocorticoid Receptor (GR)-Associated SMRT Binding to C/EBPβ TAD and Nrf2 Neh4/5: Role of SMRT Recruited to GR in GSTA2 Gene Repression
Copyright policy )Glucocorticoid Receptor (GR)-Associated SMRT Binding to C/EBPβ TAD and Nrf2 Neh4/5: Role of SMRT Recruited to GR in GSTA2 Gene Repression
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.
- Seoul National University Korea (Republic of)
Binding Sites, NF-E2-Related Factor 2, CCAAT-Enhancer-Binding Protein-beta, Down-Regulation, Acetylation, Response Elements, Dexamethasone, Cell Line, Rats, DNA-Binding Proteins, Histones, Isoenzymes, Repressor Proteins, Mice, Receptors, Glucocorticoid, Animals, Nuclear Receptor Co-Repressor 2, Promoter Regions, Genetic, Glutathione Transferase, Protein Binding
Binding Sites, NF-E2-Related Factor 2, CCAAT-Enhancer-Binding Protein-beta, Down-Regulation, Acetylation, Response Elements, Dexamethasone, Cell Line, Rats, DNA-Binding Proteins, Histones, Isoenzymes, Repressor Proteins, Mice, Receptors, Glucocorticoid, Animals, Nuclear Receptor Co-Repressor 2, Promoter Regions, Genetic, Glutathione Transferase, Protein Binding
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