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Molecular and Cellular Biology, May 2005, p. 4150-4165, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4150-4165.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Glucocorticoid Receptor (GR)-Associated SMRT Binding to C/EBPß TAD and Nrf2 Neh4/5: Role of SMRT Recruited to GR in GSTA2 Gene Repression

Sung Hwan Ki,{dagger} Il Je Cho,{dagger} Dal Woong Choi, and Sang Geon Kim*

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea

Received 13 October 2004/ Returned for modification 8 November 2004/ Accepted 5 February 2005

The expression of the glutathione S-transferase gene (GST), whose induction accounts for cancer chemoprevention, is regulated by activation of CCAAT/enhancer binding protein ß (C/EBPß) and NF-E2-related factor 2 (Nrf2). The present study investigated the repressing effects of activating glucocorticoid receptor (GR) on C/EBPß- 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/EBPß 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/EBPß 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/EBPß or Nrf2. The plasmid transfection and siRNA experiments directly evidenced the functional role of SMRT in GSTA2 repression. In conclusion, dexamethasone antagonizes C/EBPß- and Nrf2-mediated GSTA2 gene induction via ligand-GR binding to the GRE, and steroid-mediated GSTA2 repression involves inactivation of C/EBPß and Nrf2 by SMRT recruited to steroid-GR complex.

* Corresponding author. Mailing address: College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea. Phone: 822-880-7840. Fax: 822-872-1795. E-mail: sgk{at}snu.ac.kr.

{dagger} S.H.K. and I.J.C. contributed equally to this work.

Molecular and Cellular Biology, May 2005, p. 4150-4165, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.4150-4165.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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