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Receptor Chimeras1
Departments of Molecular and Integrative Physiology (E.M.M., K.E.W., J.S., B.S.K.) and Cell and Structural Biology (B.S.K.), University of Illinois, Urbana, Illinois 61801; and the Target Discovery Unit, N.V. Organon (S.M.), Oss, The Netherlands
Address all correspondence and requests for reprints to: Dr. Benita Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu
We have studied the two estrogen receptor (ER) subtypes, ER
and
ERß, and chimeric constructs with ER and ERß to examine the
bioactivities of these receptors and their responses to estrogen and
antiestrogen ligands. Transcriptional activity of ERß is highly
dependent on cell/promoter context and on the nature of the ligand.
ERß activated significant levels of transcription in response to
estrogens in certain cell types, but showed only moderate activity
compared with ER in others. Antiestrogens such as tamoxifen and
2-phenylbenzofuran, which show some agonistic activity with ER,
exhibit no agonistic activity with ERß. Alteration of the
amino-terminal A/B receptor domain can result in a dramatic change in
cell type- and ligand-specific transcriptional activity of ERß. Upon
replacing the A/B domain of ERß with the A/B domain of ER, this
receptor chimera not only exhibits an improved transcriptional response
to estrogens, but also is now able to activate transcription upon
treatment with these antiestrogens. As antiestrogen agonism was lacking
in ERß and the ERß/ chimera containing the amino-terminal A/B
domain of ERß fused to domains C through F of ER, but was restored
in an ER/ß chimera containing the A/B domain of ER,
antiestrogen agonism was shown to depend on the A/B domain (activation
function-1-containing region) of ER. Together, these results
indicate that the differences in the amino-terminal regions of ER
and ERß contribute to the cell- and promoter-specific differences in
transcriptional activity of these receptors, and their ability to
respond to different ligands, thus providing a mechanism for
differentially regulated transcription by these two ERs.
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G. Lazennec, D. Bresson, A. Lucas, C. Chauveau, and F. Vignon ER{beta} Inhibits Proliferation and Invasion of Breast Cancer Cells Endocrinology, September 1, 2001; 142(9): 4120 - 4130. [Abstract] [Full Text] [PDF]
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P. G. V. Martini and B. S. Katzenellenbogen Regulation of Prothymosin {alpha} Gene Expression by Estrogen in Estrogen Receptor-Containing Breast Cancer Cells via Upstream Half-Palindromic Estrogen Response Element Motifs Endocrinology, August 1, 2001; 142(8): 3493 - 3501. [Abstract] [Full Text] [PDF]
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O. M. Conneely Perspective: Female Steroid Hormone Action Endocrinology, June 1, 2001; 142(6): 2194 - 2199. [Full Text] [PDF]
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S. Wissink, B. van der Burg, B. S. Katzenellenbogen, and P. T. van der Saag Synergistic Activation of the Serotonin-1A Receptor by Nuclear Factor-{{kappa}}B and Estrogen Mol. Endocrinol., April 1, 2001; 15(4): 543 - 552. [Abstract] [Full Text]
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 M. E. Burow, S. M. Boue, B. M. Collins-Burow, L. I. Melnik, B. N. Duong, C. H. Carter-Wientjes, S. Li, T. E. Wiese, T. E. Cleveland, and J. A. McLachlan Phytochemical Glyceollins, Isolated from Soy, Mediate Antihormonal Effects through Estrogen Receptor {{alpha}} and {beta} J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1750 - 1758. [Abstract] [Full Text]
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M. E. Quaedackers, C. E. Van Den Brink, S. Wissink, R. H. M. M. Schreurs, J.-A. Gustafsson, P. T. Van Der Saag, and B. Van Der Burg 4-Hydroxytamoxifen Trans-Represses Nuclear Factor-{{kappa}}B Activity in Human Osteoblastic U2-OS Cells through Estrogen Receptor (ER){{alpha}}, and Not through ER{{beta}} Endocrinology, March 1, 2001; 142(3): 1156 - 1166. [Abstract] [Full Text] [PDF]
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M. Campbell-Thompson, I. J. Lynch, and B. Bhardwaj Expression of Estrogen Receptor (ER) Subtypes and ER{beta} Isoforms in Colon Cancer Cancer Res., January 1, 2001; 61(2): 632 - 640. [Abstract] [Full Text]
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J. E. Compston Sex Steroids and Bone Physiol Rev, January 1, 2001; 81(1): 419 - 447. [Abstract] [Full Text] [PDF]
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J. L. Bowers, V. V. Tyulmenkov, S. C. Jernigan, and C. M. Klinge Resveratrol Acts as a Mixed Agonist/Antagonist for Estrogen Receptors {alpha} and {beta} Endocrinology, October 1, 2000; 141(10): 3657 - 3667. [Abstract] [Full Text] [PDF]
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P. T.K. Saunders, M. R. Millar, K. Williams, S. Macpherson, D. Harkiss, R. A. Anderson, B. Orr, N. P. Groome, G. Scobie, and H. M. Fraser Differential Expression of Estrogen Receptor-{alpha} and -{beta} and Androgen Receptor in the Ovaries of Marmosets and Humans Biol Reprod, October 1, 2000; 63(4): 1098 - 1105. [Abstract] [Full Text]
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P. G. V. Martini, R. Delage-Mourroux, D. M. Kraichely, and B. S. Katzenellenbogen Prothymosin Alpha Selectively Enhances Estrogen Receptor Transcriptional Activity by Interacting with a Repressor of Estrogen Receptor Activity Mol. Cell. Biol., September 1, 2000; 20(17): 6224 - 6232. [Abstract] [Full Text]
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 F. Delaunay, K. Pettersson, M. Tujague, and J.-A. Gustafsson Functional Differences between the Amino-Terminal Domains of Estrogen Receptors alpha and beta Mol. Pharmacol., September 1, 2000; 58(3): 584 - 590. [Abstract] [Full Text]
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F. G. Petit, Y. Valotaire, and F. Pakdel The analysis of chimeric human/rainbow trout estrogen receptors reveals amino acid residues outside of P- and D-boxes important for the transactivation function Nucleic Acids Res., July 15, 2000; 28(14): 2634 - 2642. [Abstract] [Full Text] [PDF]
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D. A. Schreihofer, M. H. Stoler, and M. A. Shupnik Differential Expression and Regulation of Estrogen Receptors (ERs) in Rat Pituitary and Cell Lines: Estrogen Decreases ER{alpha} Protein and Estrogen Responsiveness Endocrinology, June 1, 2000; 141(6): 2174 - 2184. [Abstract] [Full Text] [PDF]
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C. Patrone, G. Pollio, E. Vegeto, E. Enmark, I. de Curtis, J.-A. Gustafsson, and A. Maggi Estradiol Induces Differential Neuronal Phenotypes by Activating Estrogen Receptor {alpha} or {beta} Endocrinology, May 1, 2000; 141(5): 1839 - 1845. [Abstract] [Full Text] [PDF]
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 K. Yao, E.-S. Lee, D. J. Bentrem, G. England, J. I. M. Schafer, R. M. O’Regan, and V. C. Jordan Antitumor Action of Physiological Estradiol on Tamoxifen-stimulated Breast Tumors Grown in Athymic Mice Clin. Cancer Res., May 1, 2000; 6(5): 2028 - 2036. [Abstract] [Full Text]
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G. de Haan, S. Chusacultanachai, C. Mao, B. S. Katzenellenbogen, and D. J. Shapiro Estrogen Receptor-KRAB Chimeras Are Potent Ligand-dependent Repressors of Estrogen-regulated Gene Expression J. Biol. Chem., April 28, 2000; 275(18): 13493 - 13501. [Abstract] [Full Text] [PDF]
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B. Saville, M. Wormke, F. Wang, T. Nguyen, E. Enmark, G. Kuiper, J.-A. Gustafsson, and S. Safe Ligand-, Cell-, and Estrogen Receptor Subtype (alpha /beta )-dependent Activation at GC-rich (Sp1) Promoter Elements J. Biol. Chem., February 25, 2000; 275(8): 5379 - 5387. [Abstract] [Full Text] [PDF]
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 B. S. Katzenellenbogen Mechanisms of Action and Cross-Talk Between Estrogen Receptor and Progesterone Receptor Pathways Reproductive Sciences, January 1, 2000; 7(1_suppl): S33 - S37. [Abstract] [PDF]
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K. W. Gaido, L. S. Leonard, S. C. Maness, J. M. Hall, D. P. McDonnell, B. Saville, and S. Safe Differential Interaction of the Methoxychlor Metabolite 2,2-Bis-(p-Hydroxyphenyl)-1,1,1-Trichloroethane with Estrogen Receptors {alpha} and {beta} Endocrinology, December 1, 1999; 140(12): 5746 - 5753. [Abstract] [Full Text]
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P. Webb, P. Nguyen, C. Valentine, G. N. Lopez, G. R. Kwok, E. McInerney, B. S. Katzenellenbogen, E. Enmark, J.-A. Gustafsson, S. Nilsson, et al. The Estrogen Receptor Enhances AP-1 Activity by Two Distinct Mechanisms with Different Requirements for Receptor Transactivation Functions Mol. Endocrinol., October 1, 1999; 13(10): 1672 - 1685. [Abstract] [Full Text]
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 M. M. Montano, K. Ekena, R. Delage-Mourroux, W. Chang, P. Martini, and B. S. Katzenellenbogen An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens PNAS, June 8, 1999; 96(12): 6947 - 6952. [Abstract] [Full Text] [PDF]
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L. H. Milocco, J. A. Haslam, J. Rosen, and H. M. Seidel Design of Conditionally Active STATs: Insights into STAT Activation and Gene Regulatory Function Mol. Cell. Biol., April 1, 1999; 19(4): 2913 - 2920. [Abstract] [Full Text] [PDF]
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G. B. Tremblay, A. Tremblay, F. Labrie, and V. Giguere Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor alpha -beta Heterodimeric Complex Mol. Cell. Biol., March 1, 1999; 19(3): 1919 - 1927. [Abstract] [Full Text] [PDF]
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J. Sun, M. J. Meyers, B. E. Fink, R. Rajendran, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Novel Ligands that Function as Selective Estrogens or Antiestrogens for Estrogen Receptor-{alpha} or Estrogen Receptor-{beta} Endocrinology, February 1, 1999; 140(2): 800 - 804. [Abstract] [Full Text]
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R. Delage-Mourroux, P. G. V. Martini, I. Choi, D. M. Kraichely, J. Hoeksema, and B. S. Katzenellenbogen Analysis of Estrogen Receptor Interaction with a Repressor of Estrogen Receptor Activity (REA) and the Regulation of Estrogen Receptor Transcriptional Activity by REA J. Biol. Chem., November 10, 2000; 275(46): 35848 - 35856. [Abstract] [Full Text] [PDF]
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I. Tcherepanova, P. Puigserver, J. D. Norris, B. M. Spiegelman, and D. P. McDonnell Modulation of Estrogen Receptor-alpha Transcriptional Activity by the Coactivator PGC-1 J. Biol. Chem., May 19, 2000; 275(21): 16302 - 16308. [Abstract] [Full Text] [PDF]
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R. V. Weatherman and T. S. Scanlan Unique Protein Determinants of the Subtype-selective Ligand Responses of the Estrogen Receptors (ERalpha and ERbeta ) at AP-1 Sites J. Biol. Chem., February 2, 2001; 276(6): 3827 - 3832. [Abstract] [Full Text] [PDF]
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M. Gangloff, M. Ruff, S. Eiler, S. Duclaud, J. M. Wurtz, and D. Moras Crystal Structure of a Mutant hERalpha Ligand-binding Domain Reveals Key Structural Features for the Mechanism of Partial Agonism J. Biol. Chem., April 27, 2001; 276(18): 15059 - 15065. [Abstract] [Full Text] [PDF]
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A. Warnmark, T. Almlof, J. Leers, J.-A. Gustafsson, and E. Treuter Differential Recruitment of the Mammalian Mediator Subunit TRAP220 by Estrogen Receptors ERalpha and ERbeta J. Biol. Chem., June 22, 2001; 276(26): 23397 - 23404. [Abstract] [Full Text] [PDF]
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M. A. Loven, V. S. Likhite, I. Choi, and A. M. Nardulli Estrogen Response Elements Alter Coactivator Recruitment through Allosteric Modulation of Estrogen Receptor beta Conformation J. Biol. Chem., November 21, 2001; 276(48): 45282 - 45288. [Abstract] [Full Text] [PDF]
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J. M. Hall, J. F. Couse, and K. S. Korach The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling J. Biol. Chem., September 28, 2001; 276(40): 36869 - 36872. [Full Text] [PDF]
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