| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Chemistry (A.C.G., K.E.C., J.A.K.) University of
Illinois Urbana, Illinois 61801
Department of Molecular
and Integrative Physiology (B.S.K., P.G.V.M.) University of
Illinois and University of Illinois College of Medicine Urbana,
Illinois 61801
The effectiveness of estrogens in stimulating gene
transcription mediated by the estrogen receptor (ER) appears to depend
on ER interactions with coactivator proteins. These coactivators bind
to ER when it is liganded with an estrogen agonist, but not when it is
liganded with an estrogen antagonist. Because estrogen agonists are
known to induce a conformation in ER that stabilizes coactivator
binding, we asked whether coactivator binding to ER causes a reciprocal
stabilization of agonist ligand binding. We used a fluorescent ligand
for ER, tetrahydrochrysene-ketone, to monitor the rates of
ligand dissociation from ER
and ERß, and to see how this process
is affected by the p160-class coactivator, steroid receptor
coactivator-1 (SRC-1). We used a 15-amino acid peptide corresponding to
the second nuclear receptor box LXXLL motif in SRC-1 (NR-2 peptide),
which is known to interact with the ER ligand-binding domain, a mutant
peptide with an LXXAL sequence (NR-2A peptide), and a
203-amino acid fragment of SRC-1, termed the nuclear receptor domain
(SRC1-NRD), embodying all three of the internal NR boxes of this
protein. Both the NR-2 peptide and the SRC1-NRD fragment markedly slow
the rate of dissociation of the agonist ligands
tetrahydrochrysene-ketone, estradiol, and diethylstilbestrol,
increasing the half-life of the ER-agonist complex by up to 50- to
60-fold. The SRC1-NRD has much higher potency in retarding ligand
dissociation than does the NR-2 peptide; it is maximally effective at
30 nM, and it appears to bind with the
stoichiometry of one SRC1-NRD per ER dimer. The peptides had little
effect on the dissociation rate of antagonist ligands. Consistent with
these results, we find that increasing the concentration of SRC-1 in
cells by transfection of an expression plasmid encoding SRC-1 causes a
17-fold increase in the potency of estradiol in an estrogen-responsive
reporter gene transcription assay. Thus, there is multifactorial
control over receptor-coactivator interaction, its strength being
determined by the agonist vs. antagonist nature of the
ligand and the particular structure of the agonist ligand, and by the
receptor subtype and the NR box sequence. The stabilizing effect of
coactivator on ER-agonist ligand complexes may be important in
determining the potency of estrogen agonists in a cell and may also
underlie the tissue-selective pharmacology of certain synthetic
estrogens.
This article has been cited by other articles:
 |
|
 |
|
  M. T. Sonoda, L. Martinez, P. Webb, M. S. Skaf, and I. Polikarpov Ligand Dissociation from Estrogen Receptor Is Mediated by Receptor Dimerization: Evidence from Molecular Dynamics Simulations Mol. Endocrinol., July 1, 2008; 22(7): 1565 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chang, K.-w. Peng, I. Kastrati, C. R. Overk, Z.-H. Qin, P. Yao, J. L. Bolton, and G. R. J. Thatcher Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells Endocrinology, October 1, 2007; 148(10): 4793 - 4802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Miner, W. Chang, M. S. Chapman, P. D. Finn, M. H. Hong, F. J. Lopez, K. B. Marschke, J. Rosen, W. Schrader, R. Turner, et al. An Orally Active Selective Androgen Receptor Modulator Is Efficacious on Bone, Muscle, and Sex Function with Reduced Impact on Prostate Endocrinology, January 1, 2007; 148(1): 363 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tateishi, R. Sonoo, Y.-i. Sekiya, N. Sunahara, M. Kawano, M. Wayama, R. Hirota, Y.-i. Kawabe, A. Murayama, S. Kato, et al. Turning Off Estrogen Receptor {beta}-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis Mol. Cell. Biol., November 1, 2006; 26(21): 7966 - 7976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. He, R. T. Gampe Jr., A. T. Hnat, J. L. Faggart, J. T. Minges, F. S. French, and E. M. Wilson Probing the Functional Link between Androgen Receptor Coactivator and Ligand-binding Sites in Prostate Cancer and Androgen Insensitivity J. Biol. Chem., March 10, 2006; 281(10): 6648 - 6663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tamrazi, K. E. Carlson, A. L. Rodriguez, and J. A. Katzenellenbogen Coactivator Proteins as Determinants of Estrogen Receptor Structure and Function: Spectroscopic Evidence for a Novel Coactivator-Stabilized Receptor Conformation Mol. Endocrinol., June 1, 2005; 19(6): 1516 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wang and S. S. Simons Jr. Corepressor Binding to Progesterone and Glucocorticoid Receptors Involves the Activation Function-1 Domain and Is Inhibited by Molybdate Mol. Endocrinol., June 1, 2005; 19(6): 1483 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Monroe, F. J. Secreto, M. Subramaniam, B. J. Getz, S. Khosla, and T. C. Spelsberg Estrogen Receptor {alpha} and {beta} Heterodimers Exert Unique Effects on Estrogen- and Tamoxifen-Dependent Gene Expression in Human U2OS Osteosarcoma Cells Mol. Endocrinol., June 1, 2005; 19(6): 1555 - 1568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Kim, A. Tamrazi, K. E. Carlson, and J. A. Katzenellenbogen A Proteomic Microarray Approach for Exploring Ligand-initiated Nuclear Hormone Receptor Pharmacology, Receptor Selectivity, and Heterodimer Functionality Mol. Cell. Proteomics, March 1, 2005; 4(3): 267 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Ozers, K. M. Ervin, C. L. Steffen, J. A. Fronczak, C. S. Lebakken, K. A. Carnahan, R. G. Lowery, and T. J. Burke Analysis of Ligand-Dependent Recruitment of Coactivator Peptides to Estrogen Receptor Using Fluorescence Polarization Mol. Endocrinol., January 1, 2005; 19(1): 25 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, J. Huang, P. Yi, R. A. Bambara, R. Hilf, and M. Muyan Single-Chain Estrogen Receptors (ERs) Reveal that the ER{alpha}/{beta} Heterodimer Emulates Functions of the ER{alpha} Dimer in Genomic Estrogen Signaling Pathways Mol. Cell. Biol., September 1, 2004; 24(17): 7681 - 7694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Finlay, B. York, R. H. Karas, B. L. Fanburg, H. Zhang, D. J. Kwiatkowski, and D. J. Noonan Estrogen-induced Smooth Muscle Cell Growth Is Regulated by Tuberin and Associated with Altered Activation of Platelet-derived Growth Factor Receptor-{beta} and ERK-1/2 J. Biol. Chem., May 28, 2004; 279(22): 23114 - 23122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Pearce, H. Liu, I. Radhakrishnan, M. Abdelrahim, S. Safe, and V. C. Jordan Interaction of the Aryl Hydrocarbon Receptor Ligand 6-Methyl-1,3,8-trichlorodibenzofuran with Estrogen Receptor {alpha} Cancer Res., April 15, 2004; 64(8): 2889 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Nawaz and B. W. O'Malley Urban Renewal in the Nucleus: Is Protein Turnover by Proteasomes Absolutely Required for Nuclear Receptor-Regulated Transcription? Mol. Endocrinol., March 1, 2004; 18(3): 493 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Thackray, D. O. Toft, and S. K. Nordeen Novel Activation Step Required for Transcriptional Competence of Progesterone Receptor on Chromatin Templates Mol. Endocrinol., December 1, 2003; 17(12): 2543 - 2553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tamrazi, K. E. Carlson, J. R. Daniels, K. M. Hurth, and J. A Katzenellenbogen Estrogen Receptor Dimerization: Ligand Binding Regulates Dimer Affinity and DimerDissociation Rate Mol. Endocrinol., December 1, 2002; 16(12): 2706 - 2719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Barkhem, L.-A. Haldosen, J.-A. Gustafsson, and S. Nilsson pS2 Gene Expression in HepG2 cells: Complex Regulation through Crosstalk between the Estrogen Receptor alpha , an Estrogen-Responsive Element, and the Activator Protein 1 Response Element Mol. Pharmacol., June 1, 2002; 61(6): 1273 - 1283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Heinlein and C. Chang Androgen Receptor (AR) Coregulators: An Overview Endocr. Rev., April 1, 2002; 23(2): 175 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. V. Weatherman, C.-Y. Chang, N. J. Clegg, D. C. Carroll, R. N. Day, J. D. Baxter, D. P. McDonnell, T. S. Scanlan, and F. Schaufele Ligand-Selective Interactions of ER Detected in Living Cells by Fluorescence Resonance Energy Transfer Mol. Endocrinol., March 1, 2002; 16(3): 487 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan, S. Gapstur, and M. Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease J Natl Cancer Inst, October 3, 2001; 93(19): 1449 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson Mechanisms of Estrogen Action Physiol Rev, October 1, 2001; 81(4): 1535 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Bramlett, Y. Wu, and T. P. Burris Ligands Specify Coactivator Nuclear Receptor (NR) Box Affinity for Estrogen Receptor Subtypes Mol. Endocrinol., June 1, 2001; 15(6): 909 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Gee and J. A. Katzenellenbogen Probing Conformational Changes in the Estrogen Receptor: Evidence for a Partially Unfolded Intermediate Facilitating Ligand Binding and Release Mol. Endocrinol., March 1, 2001; 15(3): 421 - 428. [Abstract] [Full Text]
|
|
|
|
|
|
F. Schaufele, C.-y. Chang, W. Liu, J. D. Baxter, S. K. Nordeen, Y. Wan, R. N. Day, and D. P. McDonnell Temporally Distinct and Ligand-Specific Recruitment of Nuclear Receptor-Interacting Peptides and Cofactors to Subnuclear Domains Containing the Estrogen Receptor Mol. Endocrinol., December 1, 2000; 14(12): 2024 - 2039. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. L. Woodward, H. Lu, and S. Z. Haslam Laminin Inhibits Estrogen Action in Human Breast Cancer Cells Endocrinology, August 1, 2000; 141(8): 2814 - 2821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Glass and M. G. Rosenfeld The coregulator exchange in transcriptional functions of nuclear receptors Genes & Dev., January 15, 2000; 14(2): 121 - 141. [Full Text]
|
|
|
|
|
|
B. He, J. A. Kemppainen, J. J. Voegel, H. Gronemeyer, and E. M. Wilson Activation Function 2 in the Human Androgen Receptor Ligand Binding Domain Mediates Interdomain Communication with the NH2-terminal Domain J. Biol. Chem., December 24, 1999; 274(52): 37219 - 37225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. He, J. A. Kemppainen, and E. M. Wilson FXXLF and WXXLF Sequences Mediate the NH2-terminal Interaction with the Ligand Binding Domain of the Androgen Receptor J. Biol. Chem., July 21, 2000; 275(30): 22986 - 22994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chen, N. J. Sarlis, and S. S. Simons Jr. Evidence for a Common Step in Three Different Processes for Modulating the Kinetic Properties of Glucocorticoid Receptor-induced Gene Transcription J. Biol. Chem., September 22, 2000; 275(39): 30106 - 30117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. An, C. Tzagarakis-Foster, T. C. Scharschmidt, N. Lomri, and D. C. Leitman Estrogen Receptor beta -Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens J. Biol. Chem., May 18, 2001; 276(21): 17808 - 17814. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
