A conserved lysine in the estrogen receptor DNA binding domain regulates ligand activation profiles at AP-1 sites, possi
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BioMed Central
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A conserved lysine in the estrogen receptor DNA binding domain regulates ligand activation profiles at AP-1 sites, possibly by controlling interactions with a modulating repressor Rosalie M Uht*1, Paul Webb2, Phuong Nguyen2, Richard H Price Jr Jr3, Cathleen Valentine4, Helene Favre4 and Peter J Kushner4 Address: 1Departments of Pathology, & Biochemistry and Molecular Genetics University of Virginia, School of Medicine, MR5 Rm. 3123, 415 Lane Rd., Charlottesville, VA 22908-0904, USA, 2Center for Diabetes and Endocrinology, University of California San Francisco, CA 94143-0540, USA, 3Amgen, Inc., 930 Scott St. #6, San Francisco, CA 94115, USA and 4Department of Medicine, Room C430, 2200 Post St., University of California San Francisco, San Francisco CA 94115-1640, USA Email: Rosalie M Uht* - [email protected]; Paul Webb - [email protected]; Phuong Nguyen - [email protected]; Richard H Price Jr - [email protected]; Cathleen Valentine - [email protected]; Helene Favre - [email protected]; Peter J Kushner - [email protected] * Corresponding author
Published: 07 May 2004 Nuclear Receptor 2004, 2:2
doi:10.1186/1478-1336-2-2
Received: 24 November 2003 Accepted: 07 May 2004
This article is available from: http://www.nuclear-receptor.com/content/2/1/2 © 2004 Uht et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract Background: Estrogen receptors alpha and beta (ERα and ERβ) differentially activate genes with AP-1 elements. ERα activates AP-1 targets via activation functions with estrogens (the AFdependent pathway), whereas ERβ, and a short version of ERα (ERα DBD-LBD) activate only with anti-estrogens (AF-independent pathway). The DNA binding domain (DBD) plays an important role in both pathways, even though neither pathway requires ERE recognition. Results: Mutations of a highly conserved DBD lysine (ERα.K206A/G), lead to super-activation of AP-1 through activation function dependent pathways, up to 200 fold. This super-activity can be elicited either through ER AFs 1 or 2, or that of a heterologous activation function (VP16). The homologous substitution in ERβ, K170A, or in ERα DBD-LBD leads to estrogen-dependent AP-1 activation and loss of the usually potent anti-estrogen effects. Each of numerous K206 substitutions in ERα, except K206R, eliminates anti-estrogen activation and this loss correlates perfectly with a loss of ability to titrate a repressive function from the RU486 bound progesterone receptor. Conclusion: We conclude that ER DBDs contain a complex regulatory function that influences ligand activation profiles at AP-1. This function, which requires the integrity of the conserved lysine, both allows for activation at AP-1 with anti-estrogens (with ERβ and ERα DBD-LBD), and prevents ERα from becoming superactive at AP-1 with estrogens. We discuss the poss
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