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Molecular and Cellular Biology, April 2004, p. 3445-3459, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3445-3459.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of Tamoxifen-Induced Coregulator Interaction Surfaces within the Ligand-Binding Domain of Estrogen Receptors

Nina Heldring,1 Maria Nilsson,1 Benjamin Buehrer,2 Eckardt Treuter,1* and Jan-Åke Gustafsson1

Department of Biosciences at Novum, Karolinska Institutet, S-14157 Huddinge, Sweden,1 KaroBio Inc., Durham, North Carolina 277032

Received 4 August 2003/ Returned for modification 9 September 2003/ Accepted 19 January 2004

Tamoxifen is a selective estrogen receptor (ER) modulator that is clinically used as an antagonist to treat estrogen-dependent breast cancers but displays unwanted agonistic effects in other tissues. Previous studies on ER{alpha} have delineated a role of the N-terminal activation function AF-1 in mediating the agonistic effects of tamoxifen, while the mechanisms for how ERß mediates tamoxifen action remain to be elucidated. As peptides can be used to detect distinct receptor conformations and binding surfaces for coactivators and corepressors, we attempted in this study to identify previously unrecognized peptides that interact specifically with ERs in the presence of tamoxifen. We identified two distinct peptides among others that are highly selective for tamoxifen-bound ER{alpha} or ERß. Domain mapping and mutation analysis suggest that these peptides recognize a novel tamoxifen-induced binding surface within the C-terminal ligand-binding domain that is distinct from the agonist-induced AF-2 surface. Peptide expression specifically inhibited transcriptional ER activity in response to tamoxifen, presumably by preventing the binding of endogenous coactivators. Moreover, tamoxifen-responsive and ER subtype-selective coactivators were engineered by replacing the LXXLL motifs in the coactivator TIF2 with either of the two peptides. Finally, our results indicate that related coactivators may act via the novel tamoxifen-induced binding surface, referred to as AF-T, allowing us to propose a revised model of tamoxifen agonism.

* Corresponding author. Mailing address: Department of Biosciences at Novum, Karolinska Institutet, S-14157 Huddinge, Sweden. Phone: 46-8-6089162. Fax: 46-8-7745538. E-mail: eckardt.treuter{at}cbt.ki.se.

Molecular and Cellular Biology, April 2004, p. 3445-3459, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3445-3459.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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