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Originally published In Press as doi:10.1074/jbc.M002497200 on June 5, 2000

J. Biol. Chem., Vol. 275, Issue 33, 25322-25329, August 18, 2000
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Mutations in the Estrogen Receptor Ligand Binding Domain Discriminate between Hormone-dependent Transactivation and Transrepression*

Janet E. ValentineDagger , Eric Kalkhoven§, Roger White, Sue Hoare, and Malcolm G. Parker

From the Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

The estrogen receptor (ER) suppresses transcriptional activity of the RelA subunit of nuclear factor-kappa B in a hormone-dependent manner by a mechanism involving both the receptor DNA binding domain and ligand binding domain (LBD). In this study we examine the role of the ER LBD in mediating ligand-dependent RelA transrepression. Both ERalpha and ERbeta inhibit RelA in response to 17beta -estradiol but not in the presence of antihormones. We have identified residues within the ERalpha LBD that are responsible for receptor dimerization and show that dimerization is necessary for transactivation and transrepression. Moreover we have generated mutant receptors that have lost their ability to inhibit RelA but retain their capacity to stimulate transcription and conversely mutants that are transcriptionally defective but capable of antagonizing RelA. Overexpression of p160 and cAMP-response element-binding protein-binding protein/p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators. These findings suggest it is unlikely that sequestration of these cofactors required for ER transcriptional activation can account for hormone-dependent antagonism of RelA. The identification of ER mutants that discriminate between transactivation and transrepression implies that distinct surfaces within the LBD are involved in mediating these two receptor functions.

* This research was supported by grants from the International Association for Cancer Research (to J. E. V.) and the Netherlands Organization for Scientific Research (NWO) (to E. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Breakthrough Toby Robins Breast Cancer Centre, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, UK.

§ Present address: Laboratory for Molecular Carcinogenesis, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

To whom correspondence should be addressed. Tel.: 44 207 269 3280; Fax: 44 207 269 3094; E-mail: M.Parker@icrf.icnet.uk.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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