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Molecular and Cellular Biology, September 2007, p. 5933-5948, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00237-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Corepressor Is Required for Full Estrogen Receptor {alpha} Transcriptional Activity{triangledown}

Theresa J. Peterson,{dagger} Sudipan Karmakar, Margaret C. Pace, Tong Gao, and Carolyn L. Smith*

Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Received 9 February 2007/ Returned for modification 13 March 2007/ Accepted 15 June 2007

Multiple factors influence estrogen receptor {alpha} (ER{alpha}) transcriptional activity. Current models suggest that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor functions within a histone deactylase-containing protein complex that binds to antiestrogen-bound ER{alpha} and contributes to negative regulation of gene expression. In this report, we demonstrate that SMRT is required for full agonist-dependent ER{alpha} activation. Chromatin immunoprecipitation assays demonstrate that SMRT, like ER{alpha} and the SRC-3 coactivator, is recruited to an estrogen-responsive promoter in estrogen-treated MCF-7 cells. Depletion of SMRT, but not histone deacetylases 1 or 3, negatively impacts estradiol-stimulated ER{alpha} transcriptional activity, while exogenous expression of SMRT's receptor interaction domains blocks ER{alpha} activity, indicating a functional interaction between this corepressor and agonist-bound ER{alpha}. Stimulation of estradiol-induced ER{alpha} activity by SMRT overexpression occurred in HeLa and MCF-7 cells, but not HepG2 cells, indicating that these positive effects are cell type specific. Similarly, the ability of SMRT depletion to promote the agonist activity of tamoxifen was observed for HeLa but not MCF-7 cells. Furthermore, impairment of agonist-stimulated activity by SMRT depletion is specific to ER{alpha} and not observed for receptors for vitamin D, androgen, or thyroid hormone. Nuclear receptor corepressor (N-CoR) depletion increased the transcriptional activity of all four tested receptors. SMRT is required for full expression of the ER{alpha} target genes cyclin D1, BCL-2, and progesterone receptor but not pS2, and its depletion significantly attenuated estrogen-dependent proliferation of MCF-7 cells. Taken together, these data indicate that SMRT, in conjunction with gene-specific and cell-dependent factors, is required for positively regulating agonist-dependent ER{alpha} transcriptional activity.

* Corresponding author. Mailing address: Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-6235. Fax: (713) 790-1275. E-mail: carolyns{at}bcm.tmc.edu

{triangledown} Published ahead of print on 25 June 2007.

{dagger} Present address: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, The Feinberg School of Medicine, Chicago, IL 60611.

Molecular and Cellular Biology, September 2007, p. 5933-5948, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00237-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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