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J. Biol. Chem., Vol. 281, Issue 24, 16272-16278, June 16, 2006

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Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter^*

Fabio Stossi, Varsha S. Likhite¹, John A. Katzenellenbogen, and Benita S. Katzenellenbogen^¶2

From the Department of Molecular and Integrative Physiology, Department of Chemistry, and ^¶Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Estrogens, acting through their nuclear receptors have a broad impact on target cells, eliciting a transcriptional response program that involves gene repression as well as gene stimulation. While much is known about the mechanisms by which the estrogen-occupied estrogen receptor (ER) stimulates gene expression, the molecular events that lead to gene repression by the hormone-ER complex are largely unknown. Because estradiol represses expression of the cyclin G2 gene, which encodes a negative regulator of the cell cycle, our aim was to understand the mechanism by which cyclin G2 is repressed by estrogen. We show that cyclin G2 is a primary ER target gene in MCF-7 breast cancer cells that is rapidly and robustly down-regulated by estrogen. Promoter analysis reveals a responsive region containing a half-estrogen response element and GC-rich region that interact with ER and Sp1 proteins. Mutation of the half-ERE abrogates hormone-mediated repression. Mutational mapping of receptor reveals a requirement for its N-terminal region and DNA binding domain to support cyclin G2 repression. Following estradiol treatment of cells, chromatin immunoprecipitation analyses reveal recruitment of ER to the cyclin G2 regulatory region, dismissal of RNA polymerase II, and recruitment of a complex containing N-CoR and histone deacetylases, leading to a hypoacetylated chromatin state. Our study provides evidence for a mechanism by which the estrogen-occupied ER is able to actively repress gene expression in vivo and indicates a role for nuclear receptor corepressors and associated histone deacetylase activity in mediating negative gene regulation by this hormone-occupied nuclear receptor.

Received for publication, December 16, 2005 , and in revised form, April 10, 2006.

^* This work was supported by National Institutes of Health Grant CA 18119 and by the Breast Cancer Research Foundation (both to B. S. K.) and National Institutes of Health Grant DK15556 (to J. A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grant T32 ES-07326.

² To whom correspondence should be addressed: University of Illinois, Dept. of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Ave., Urbana, IL 61801-3704. Tel.: 217-333-9769; Fax: 217-244-9906; E-mail: katzenel{at}uiuc.edu.

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