| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Dr. Kenneth Korach, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709.
Abstract
The antiestrogen ICI 164,384 (ICI) binds the estrogen receptor (ER) with approximately 20% the affinity of estradiol, but without the partial agonistic effects caused by tamoxifen. Investigations into the mechanism of ICI action have used ER molecules expressed in vitro to examine the binding of ER to ICI and the capacity of ICI-ER complexes to dimerize and bind to the estrogen response element (ERE), Our objectives were to study the biological effects, cellular distribution, and ERE-binding capacity of native uterine ICI-ER complexes after ip injection of 1 mg/kg ICI into 10-day castrate adult female mice. Synthesis of DNA and progesterone receptor were measured as end points of agonistic activity. ICI failed to stimulate either DNA or progesterone receptor synthesis above control levels, and pretreatment with ICI for 0.5 h reduced the stimulatory effect of estradiol by 75%. Measurement of uterine nuclear ER and cytosolic levels by exchange binding assay indicated a reduction in total ER levels within 0.5 h after ICI treatment, which remained below 20% for 24 h. Cycloheximide treatment did not block the ICI effect. Western blot analysis, immunohistochemistry, and steroid autoradiography confirmed the loss of ER protein. The ICI effect on ER was also demonstrable in vitro in the mouse TM4 estrogen-responsive cell line. ICI dramatically reduced ER levels to 5% of the control value by 4 h. Northern analysis indicated that ICI did not affect ER message levels, suggesting that the observed reduction in ER did not occur at the level of transcription. Gel shift assays indicated a low, but detectable, amount of ICI-ER binding to the vitellogenin A2 (VitA2) ERE. These results suggest that, although the ICI-ER complex binds weakly to DNA, ICI may cause its antagonistic effect by producing a rapid disappearance of the ER from the target tissue, resulting in an insufficient amount of ER to bind the native ligand and elicit agonist responses.(Endocrinology 129: 2000-2010, 1991)
Received April 19, 1991.
This article has been cited by other articles:
![]() |
W. Yan, J. Chen, A. A Wiley, B. D Crean-Harris, F. F Bartol, and C. A Bagnell Relaxin (RLX) and estrogen affect estrogen receptor {alpha}, vascular endothelial growth factor, and RLX receptor expression in the neonatal porcine uterus and cervix Reproduction, May 1, 2008; 135(5): 705 - 712. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Chia, W. Gradishar, L. Mauriac, J. Bines, F. Amant, M. Federico, L. Fein, G. Romieu, A. Buzdar, J. F.R. Robertson, et al. Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor-Positive, Advanced Breast Cancer: Results From EFECT J. Clin. Oncol., April 1, 2008; 26(10): 1664 - 1670. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Zhu and J. W. Pollard Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling PNAS, October 2, 2007; 104(40): 15847 - 15851. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al. Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12 Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816. [Abstract] [Full Text] [PDF] |
||||
![]() |
W. Yan, P. L Ryan, F. F Bartol, and C. A Bagnell Uterotrophic effects of relaxin related to age and estrogen receptor activation in neonatal pigs. Reproduction, May 1, 2006; 131(5): 943 - 950. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. F. Zheng, R.-C. Wu, C. L. Smith, and B. W. O'Malley Rapid Estrogen-Induced Phosphorylation of the SRC-3 Coactivator Occurs in an Extranuclear Complex Containing Estrogen Receptor Mol. Cell. Biol., September 15, 2005; 25(18): 8273 - 8284. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Curtis Hewitt, J. Collins, S. Grissom, B. Deroo, and K. S. Korach Global Uterine Genomics in Vivo: Microarray Evaluation of the Estrogen Receptor {alpha}-Growth Factor Cross-Talk Mechanism Mol. Endocrinol., March 1, 2005; 19(3): 657 - 668. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Sonneveld, H. J. Jansen, J. A. C. Riteco, A. Brouwer, and B. van der Burg Development of Androgen- and Estrogen-Responsive Bioassays, Members of a Panel of Human Cell Line-Based Highly Selective Steroid-Responsive Bioassays Toxicol. Sci., January 1, 2005; 83(1): 136 - 148. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. A. Oliveira, Q. Zhou, K. Carnes, R. Nie, D. E. Kuehl, G. L. Jackson, L. R. Franca, M. Nakai, and R. A. Hess ER Function in the Adult Male Rat: Short- and Long-Term Effects of the Antiestrogen ICI 182,780 on the Testis and Efferent Ductules, without Changes in Testosterone Endocrinology, June 1, 2002; 143(6): 2399 - 2409. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. D. Papaconstantinou, B. R. Fisher, T. H. Umbreit, P. L. Goering, N. T. Lappas, and K. M. Brown Effects of {beta}-Estradiol and Bisphenol A on Heat Shock Protein Levels and Localization in the Mouse Uterus Are Antagonized by the Antiestrogen ICI 182,780 Toxicol. Sci., October 1, 2001; 63(2): 173 - 180. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Dowsett, N. J. Bundred, A. Decensi, R. C. Sainsbury, Y. Lu, M. J. Hills, F. J. Cohen, P. Veronesi, M. E. R. O'Brien, T. Scott, et al. Effect of Raloxifene on Breast Cancer Cell Ki67 and Apoptosis: A Double-Blind, Placebo-controlled, Randomized Clinical Trial in Postmenopausal Patients Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 961 - 966. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. A. Oliveira, K. Carnes, L. R. Franca, and R. A. Hess Infertility and Testicular Atrophy in the Antiestrogen-Treated Adult Male Rat Biol Reprod, September 1, 2001; 65(3): 913 - 920. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. C. Jordan Selective Estrogen Receptor Modulation: A Personal Perspective Cancer Res., August 1, 2001; 61(15): 5683 - 5687. [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
![]() |
S. Masuda, T. Kobayashi, M. Chikuma, M. Nagao, and R. Sasaki The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1038 - E1044. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. T. Alarid, N. Bakopoulos, and N. Solodin Proteasome-Mediated Proteolysis of Estrogen Receptor: A Novel Component in Autologous Down-Regulation Mol. Endocrinol., September 1, 1999; 13(9): 1522 - 1534. [Abstract] [Full Text] |
||||
![]() |
J. I. MacGregor Schafer, H. Liu, D. A. Tonetti, and V. C. Jordan The Interaction of Raloxifene and the Active Metabolite of the Antiestrogen EM-800 (SC 5705) with the Human Estrogen Receptor Cancer Res., September 1, 1999; 59(17): 4308 - 4313. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. J. Tarleton, A. A. Wiley, and F. F. Bartol Endometrial Development and Adenogenesis in the Neonatal Pig: Effects of Estradiol Valerate and the Antiestrogen ICI 182,780 Biol Reprod, July 1, 1999; 61(1): 253 - 263. [Abstract] [Full Text] |
||||
![]() |
S. W. Curtis, J. Clark, P. Myers, and K. S. Korach Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor alpha knockout mouse uterus PNAS, March 30, 1999; 96(7): 3646 - 3651. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Chen, P. E. Pace, R. C. Coombes, and S. Ali Phosphorylation of Human Estrogen Receptor alpha by Protein Kinase A Regulates Dimerization Mol. Cell. Biol., February 1, 1999; 19(2): 1002 - 1015. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. B. Joel, A. M. Traish, and D. A. Lannigan Estradiol-induced Phosphorylation of Serine 118 in the Estrogen Receptor Is Independent of p42/p44 Mitogen-activated Protein Kinase J. Biol. Chem., May 22, 1998; 273(21): 13317 - 13323. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Martel, C. Labrie, A. Belanger, S. Gauthier, Y. Merand, X. Li, L. Provencher, B. Candas, and F. Labrie Comparison of the Effects of the New Orally Active Antiestrogen EM-800 with ICI 182 780 and Toremifene on Estrogen-Sensitive Parameters in the Ovariectomized Mouse Endocrinology, May 1, 1998; 139(5): 2486 - 2492. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. G. Acuff, H. Huang, and M. E. Steinhelper Estradiol induces C-type natriuretic peptide gene expression in mouse uterus Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2672 - H2677. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Pace, J. Taylor, S. Suntharalingam, R. C. Coombes, and S. Ali Human Estrogen Receptor beta Binds DNA in a Manner Similar to and Dimerizes with Estrogen Receptor alpha J. Biol. Chem., October 10, 1997; 272(41): 25832 - 25838. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. A. Dipippo and C. A. Powers Tamoxifen and ICI 182,780 Interactions with Thyroid Hormone in the Ovariectomized-Thyroidectomized Rat J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 142 - 148. [Abstract] [Full Text] |
||||
![]() |
C. W. Kuil, C. A. Berrevoets, and E. Mulder Ligand-induced Conformational Alterations of the Androgen Receptor Analyzed by Limited Trypsinization J. Biol. Chem., November 17, 1995; 270(46): 27569 - 27576. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Wang, G. A. Peters, X. Zeng, M. Tang, W. Ip, and S. A. Khan Yeast Two-hybrid System Demonstrates That Estrogen Receptor Dimerization Is Ligand-dependent in Vivo J. Biol. Chem., October 6, 1995; 270(40): 23322 - 23329. [Abstract] [Full Text] [PDF] |
||||
![]() |
S Dauvois, R White, and M. Parker The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling J. Cell Sci., January 12, 1993; 106(4): 1377 - 1388. [Abstract] [PDF] |
||||
![]() |
M. W. Dudley, C. Q. Sheeler, H. Wang, and S. Khan Activation of the human estrogen receptor by the antiestrogens ICI 182,780 and tamoxifen in yeast genetic systems: Implications for their mechanism of action PNAS, March 28, 2000; 97(7): 3696 - 3701. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. T. Preisler-Mashek, N. Solodin, B. L. Stark, M. K. Tyriver, and E. T. Alarid Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E891 - E898. [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 |