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Science 30 July 1999:
Vol. 285. no. 5428, pp. 744 - 746
DOI: 10.1126/science.285.5428.744
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Reports

Peptide Antagonists of the Human Estrogen Receptor

John D. Norris, 1 Lisa A. Paige, 2 Dale J. Christensen, 2 Ching-Yi Chang, 1 Maria R. Huacani, 1 Daju Fan, 1 Paul T. Hamilton, 2 Dana M. Fowlkes, 2 Donald P. McDonnell 1*

Estrogen receptor alpha  transcriptional activity is regulated by distinct conformational states that are the result of ligand binding. Phage display was used to identify peptides that interact specifically with either estradiol- or tamoxifen-activated estrogen receptor alpha . When these peptides were coexpressed with estrogen receptor alpha  in cells, they functioned as ligand-specific antagonists, indicating that estradiol-agonist and tamoxifen-partial agonist activities do not occur by the same mechanism. The ability to regulate estrogen receptor alpha  transcriptional activity by targeting sites outside of the ligand-binding pocket has implications for the development of estrogen receptor alpha  antagonists for the treatment of tamoxifen-refractory breast cancers.

1 Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710, USA.
2 Novalon Pharmaceutical Corporation, 4222 Emperor Boulevard, Suite 560, Durham, NC 27703, USA.
*   To whom correspondence should be addressed. E-mail: mcdon016{at}acpub.duke.edu

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Ligand-, Cell-, and Estrogen Receptor Subtype (alpha /beta )-dependent Activation at GC-rich (Sp1) Promoter Elements.
B. Saville, M. Wormke, F. Wang, T. Nguyen, E. Enmark, G. Kuiper, J.-A. Gustafsson, and S. Safe (2000)
J. Biol. Chem. 275, 5379-5387
   Abstract »    Full Text »    PDF »
Molecular determinants of nuclear receptor-corepressor interaction.
V. Perissi, L. M. Staszewski, E. M. McInerney, R. Kurokawa, A. Krones, D. W. Rose, M. H. Lambert, M. V. Milburn, C. K. Glass, and M. G. Rosenfeld (1999)
Genes & Dev. 13, 3198-3208
   Abstract »    Full Text »
Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors alpha and beta.
C.-y. Chang, J. D. Norris, H. Gron, L. A. Paige, P. T. Hamilton, D. J. Kenan, D. Fowlkes, and D. P. McDonnell (1999)
Mol. Cell. Biol. 19, 8226-8239
   Abstract »    Full Text »    PDF »
Tamoxifen Prevention of Breast Cancer: an Instance of the Fingerpost.
S. M. Lippman and P. H. Brown (1999)
J Natl Cancer Inst 91, 1809-1819
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Analysis of Estrogen Receptor Interaction with a Repressor of Estrogen Receptor Activity (REA) and the Regulation of Estrogen Receptor Transcriptional Activity by REA.
R. Delage-Mourroux, P. G. V. Martini, I. Choi, D. M. Kraichely, J. Hoeksema, and B. S. Katzenellenbogen (2000)
J. Biol. Chem. 275, 35848-35856
   Abstract »    Full Text »    PDF »
Modulation of Estrogen Receptor-alpha Transcriptional Activity by the Coactivator PGC-1.
I. Tcherepanova, P. Puigserver, J. D. Norris, B. M. Spiegelman, and D. P. McDonnell (2000)
J. Biol. Chem. 275, 16302-16308
   Abstract »    Full Text »    PDF »
Identification and Characterization of a Novel Factor That Regulates Quinone Reductase Gene Transcriptional Activity.
M. M. Montano, B. M. Wittmann, and N. R. Bianco (2000)
J. Biol. Chem. 275, 34306-34313
   Abstract »    Full Text »    PDF »
Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects.
Y. Xie, M. A. Tisi, T. T. Yeo, and F. M. Longo (2000)
J. Biol. Chem. 275, 29868-29874
   Abstract »    Full Text »    PDF »
Unique Protein Determinants of the Subtype-selective Ligand Responses of the Estrogen Receptors (ERalpha and ERbeta ) at AP-1 Sites.
R. V. Weatherman and T. S. Scanlan (2001)
J. Biol. Chem. 276, 3827-3832
   Abstract »    Full Text »    PDF »
An Antiestrogen-responsive Estrogen Receptor-alpha Mutant (D351Y) Shows Weak AF-2 Activity in the Presence of Tamoxifen.
P. Webb, P. Nguyen, C. Valentine, R. V. Weatherman, T. S. Scanlan, and P. J. Kushner (2000)
J. Biol. Chem. 275, 37552-37558
   Abstract »    Full Text »    PDF »
Differential Recruitment of the Mammalian Mediator Subunit TRAP220 by Estrogen Receptors ERalpha and ERbeta.
A. Warnmark, T. Almlof, J. Leers, J.-A. Gustafsson, and E. Treuter (2001)
J. Biol. Chem. 276, 23397-23404
   Abstract »    Full Text »    PDF »
Acyl-CoA Esters Antagonize the Effects of Ligands on Peroxisome Proliferator-activated Receptor alpha Conformation, DNA Binding, and Interaction with Co-factors.
M. Elholm, I. Dam, C. Jorgensen, A.-M. Krogsdam, D. Holst, I. Kratchmarova, M. Gottlicher, J.-A. Gustafsson, R. Berge, T. Flatmark, et al. (2001)
J. Biol. Chem. 276, 21410-21416
   Abstract »    Full Text »    PDF »
The Human Estrogen Receptor-alpha Is a Ubiquitinated Protein Whose Stability Is Affected Differentially by Agonists, Antagonists, and Selective Estrogen Receptor Modulators.
A. L. Wijayaratne and D. P. McDonnell (2001)
J. Biol. Chem. 276, 35684-35692
   Abstract »    Full Text »    PDF »
Ternary Complexes and Cooperative Interplay between NCoA-62/Ski-interacting Protein and Steroid Receptor Coactivators in Vitamin D Receptor-mediated Transcription.
C. Zhang, T. A. Baudino, D. R. Dowd, H. Tokumaru, W. Wang, and P. N. MacDonald (2001)
J. Biol. Chem. 276, 40614-40620
   Abstract »    Full Text »    PDF »
The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling.
J. M. Hall, J. F. Couse, and K. S. Korach (2001)
J. Biol. Chem. 276, 36869-36872
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Probing protein conformational changes in living cells by using designer binding proteins: Application to the estrogen receptor.
A. Koide, S. Abbatiello, L. Rothgery, and S. Koide (2002)
PNAS 99, 1253-1258
   Abstract »    Full Text »    PDF »


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