This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heldring, N. Articles by Gustafsson, J.-A. Search for Related Content PubMed PubMed Citation Articles by Heldring, N. Articles by Gustafsson, J.-A.

 Previous Article  |  Next Article 

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

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 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 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.

This article has been cited by other articles:

• Rytinki, M. M., Palvimo, J. J. (2008). SUMOylation Modulates the Transcription Repressor Function of RIP140. J. Biol. Chem. 283: 11586-11595 [Abstract] [Full Text]  
• Kressler, D., Hock, M. B., Kralli, A. (2007). Coactivators PGC-1beta and SRC-1 Interact Functionally to Promote the Agonist Activity of the Selective Estrogen Receptor Modulator Tamoxifen. J. Biol. Chem. 282: 26897-26907 [Abstract] [Full Text]  
• Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Strom, A., Treuter, E., Warner, M., Gustafsson, J.-A. (2007). Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 87: 905-931 [Abstract] [Full Text]  
• Heldring, N., Pawson, T., McDonnell, D., Treuter, E., Gustafsson, J.-A., Pike, A. C. W. (2007). Structural Insights into Corepressor Recognition by Antagonist-bound Estrogen Receptors. J. Biol. Chem. 282: 10449-10455 [Abstract] [Full Text]  
• Jaber, B. M., Gao, T., Huang, L., Karmakar, S., Smith, C. L. (2006). The Pure Estrogen Receptor Antagonist ICI 182,780 Promotes a Novel Interaction of Estrogen Receptor-{alpha} with the 3',5'-Cyclic Adenosine Monophosphate Response Element-Binding Protein-Binding Protein/p300 Coactivators. Mol. Endocrinol. 20: 2695-2710 [Abstract] [Full Text]  
• Chang, E. C., Frasor, J., Komm, B., Katzenellenbogen, B. S. (2006). Impact of Estrogen Receptor {beta} on Gene Networks Regulated by Estrogen Receptor {alpha} in Breast Cancer Cells. Endocrinology 147: 4831-4842 [Abstract] [Full Text]  
• Frasor, J., Chang, E. C., Komm, B., Lin, C.-Y., Vega, V. B., Liu, E. T., Miller, L. D., Smeds, J., Bergh, J., Katzenellenbogen, B. S. (2006). Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome.. Cancer Res. 66: 7334-7340 [Abstract] [Full Text]  
• Keeton, E. K., Brown, M. (2005). Cell Cycle Progression Stimulated by Tamoxifen-Bound Estrogen Receptor-{alpha} and Promoter-Specific Effects in Breast Cancer Cells Deficient in N-CoR and SMRT. Mol. Endocrinol. 19: 1543-1554 [Abstract] [Full Text]  
• Kong, E. H., Heldring, N., Gustafsson, J.-A., Treuter, E., Hubbard, R. E., Pike, A. C. W. (2005). Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor. Proc. Natl. Acad. Sci. USA 102: 3593-3598 [Abstract] [Full Text]  
• Ozers, M. S., Ervin, K. M., Steffen, C. L., Fronczak, J. A., Lebakken, C. S., Carnahan, K. A., Lowery, R. G., Burke, T. J. (2005). Analysis of Ligand-Dependent Recruitment of Coactivator Peptides to Estrogen Receptor Using Fluorescence Polarization. Mol. Endocrinol. 19: 25-34 [Abstract] [Full Text]