| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Molecular and Integrative Physiology (G.L., L.N.P., A.M.N., B.S.K.) and Department of Cell and Structural Biology (T.R.E., B.S.K.) University of Illinois Urbana, Illinois 61801
The estrogen receptor (ER) belongs to a large family of nuclear receptors, many of whose members function as ligand-dependent transcriptional activators. The mechanism by which the receptor is converted from an inactive into an activated state is not yet completely understood. To investigate the kind of changes in receptor conformation and interactions that are involved in this activation, we have used the wild type ER and a set of constitutively active ER point mutants that show from 20% to nearly 100% activity in the absence of estrogen. These mutants are of particular interest as they could mimic, in the absence of ligand, the activated state of the wild type receptor. We have analyzed several transcriptional steps that could be involved in the activation: the ability of these receptors 1) to interact with several coactivators (steroid receptor coactivator-1, SRC-1; transcription intermediary factor-1, TIF-1; and estrogen receptor-associated protein 140, ERAP 140) and with members of the preinitiation complex [TATA box-binding protein (TBP), transcription factor IIB (TFIIB)]; 2) to exhibit conformational changes revealed by proteolytic digest patterns similar to those observed for the wild type hormone-occupied ER; and 3) to bend estrogen response element-containing DNA, which is thought to be one of the important phenomena triggering transcriptional activation. Our results demonstrate that the interaction of these mutant receptors with coactivators is likely to be one of the features of the activated step, as the mutant receptors interacted with some coactivators in a ligand-independent manner in proportion to their extent of constitutive activity. However, the different degrees of ligand-independent interaction of the mutant ERs with the three coactivators suggest that SRC-1, TIF-1, and ERAP 140 may play different roles in receptor activity. Limited proteolytic digest experiments reveal that the activated state of the receptor corresponds to a particular conformation of the receptor, which is fully observed with the mutant ER showing the highest activity in the absence of estrogen. Finally, it appears that in inactive or active states, the receptor exhibits distinctly different DNA-bending abilities. Addition of estradiol is able to modify the bending ability of only the wild type receptor, whereas estradiol has no influence on the constitutive receptors, which exhibited the same bending ability as that observed for the ligand-occupied wild type receptor. These data document that the ER undergoes major changes in its conformation and also in its functional properties when it is turned from an inactive into an active state and that mutational changes in the ER protein that result in constitutive, hormone-independent activation mimic many of the changes in ER properties that are normally under hormone regulation.
This article has been cited by other articles:
 |
|
 |
|
  J. Keay, J. T. Bridgham, and J. W. Thornton The Octopus vulgaris Estrogen Receptor Is a Constitutive Transcriptional Activator: Evolutionary and Functional Implications Endocrinology, August 1, 2006; 147(8): 3861 - 3869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Stossi, V. S. Likhite, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter J. Biol. Chem., June 16, 2006; 281(24): 16272 - 16278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kim, M. H. Lee, B. J. Kim, J. H. Kim, S. J. Han, H. Y. Kim, and M. R Stallcup Role of aspartate 351 in transactivation and active conformation of estrogen receptor {alpha} J. Mol. Endocrinol., December 1, 2005; 35(3): 449 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Farboud and M. L. Privalsky Retinoic Acid Receptor-{alpha} Is Stabilized in a Repressive State by Its C-Terminal, Isotype-Specific F Domain Mol. Endocrinol., December 1, 2004; 18(12): 2839 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Yi, M. D. Driscoll, J. Huang, S. Bhagat, R. Hilf, R. A. Bambara, and M. Muyan The Effects of Estrogen-Responsive Element- and Ligand-Induced Structural Changes on the Recruitment of Cofactors and Transcriptional Responses by ER{alpha} and ER{beta} Mol. Endocrinol., April 1, 2002; 16(4): 674 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Schultz, M. A. Loven, V. M. S. Melvin, D. P. Edwards, and A. M. Nardulli Differential Modulation of DNA Conformation by Estrogen Receptors alpha and beta J. Biol. Chem., March 1, 2002; 277(10): 8702 - 8707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Metivier, G. Penot, G. Flouriot, and F. Pakdel Synergism Between ER{alpha} Transactivation Function 1 (AF-1) and AF-2 Mediated by Steroid Receptor Coactivator Protein-1: Requirement for the AF-1 {alpha}-Helical Core and for a Direct Interaction Between the N- and C-Terminal Domains Mol. Endocrinol., November 1, 2001; 15(11): 1953 - 1970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. M. Tolón, A. I. Castillo, A. M. Jiménez-Lara, and A. Aranda Association with Ets-1 Causes Ligand- and AF2-Independent Activation of Nuclear Receptors Mol. Cell. Biol., December 1, 2000; 20(23): 8793 - 8802. [Abstract] [Full Text]
|
|
|
|
|
|
G. Lazennec, L. Canaple, D. Saugy, and W. Wahli Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators Mol. Endocrinol., December 1, 2000; 14(12): 1962 - 1975. [Abstract] [Full Text]
|
|
|
|
|
|
C. M. Bula, J. E. Bishop, S. Ishizuka, and A. W. Norman 25-Dehydro-1{alpha}-Hydroxyvitamin D3- 26,23S-Lactone Antagonizes the Nuclear Vitamin D Receptor by Mediating a Unique Noncovalent Conformational Change Mol. Endocrinol., November 1, 2000; 14(11): 1788 - 1796. [Abstract] [Full Text]
|
|
|
|
|
|
F. Gay, I. Anglade, Z. Gong, and G. Salbert The LIM/Homeodomain Protein Islet-1 Modulates Estrogen Receptor Functions Mol. Endocrinol., October 1, 2000; 14(10): 1627 - 1648. [Abstract] [Full Text]
|
|
|
|
|
|
D. M. Kraichely, J. Sun, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Conformational Changes and Coactivator Recruitment by Novel Ligands for Estrogen Receptor-{alpha} and Estrogen Receptor-{beta}: Correlations with Biological Character and Distinct Differences among SRC Coactivator Family Members Endocrinology, October 1, 2000; 141(10): 3534 - 3545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Misiti, S. Nanni, G. Fontemaggi, Y.-S. Cong, J. Wen, H. W. Hirte, G. Piaggio, A. Sacchi, A. Pontecorvi, S. Bacchetti, et al. Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells Mol. Cell. Biol., June 1, 2000; 20(11): 3764 - 3771. [Abstract] [Full Text]
|
|
|
|
|
|
A. Schlegel, C. Wang, B. S. Katzenellenbogen, R. G. Pestell, and M. P. Lisanti Caveolin-1 Potentiates Estrogen Receptor alpha (ERalpha ) Signaling. CAVEOLIN-1 DRIVES LIGAND-INDEPENDENT NUCLEAR TRANSLOCATION AND ACTIVATION OF ERalpha J. Biol. Chem., November 19, 1999; 274(47): 33551 - 33556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Jones, E. Parrott, and I. N. H. White Activation of Transcription by Estrogen Receptor alpha and beta Is Cell Type- and Promoter-dependent J. Biol. Chem., November 5, 1999; 274(45): 32008 - 32014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Sladek, M. D. Ruse Jr., L. Nepomuceno, S.-M. Huang, and M. R. Stallcup Modulation of Transcriptional Activation and Coactivator Interaction by a Splicing Variation in the F Domain of Nuclear Receptor Hepatocyte Nuclear Factor 4alpha 1 Mol. Cell. Biol., October 1, 1999; 19(10): 6509 - 6522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Wu, M. C. Thomas, S. Y. Hou, V. Likhite, and C. M. Chiang Isolation of Mouse TFIID and Functional Characterization of TBP and TFIID in Mediating Estrogen Receptor and Chromatin Transcription J. Biol. Chem., August 13, 1999; 274(33): 23480 - 23490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
F. Schaufele Regulation of Estrogen Receptor Activation of the Prolactin Enhancer/Promoter by Antagonistic Activation Function-2-Interacting Proteins Mol. Endocrinol., June 1, 1999; 13(6): 935 - 945. [Abstract] [Full Text]
|
|
|
|
 |
|
 Proceedings of the British Toxicology Society Autumn Meeting University of York 20-22 September 1998 Human and Experimental Toxicology, January 1, 1999; 18(1): 46 - 65. [PDF]
|
|
|
|
|
|
Z. Zhang and C. T. Teng Estrogen Receptor-related Receptor alpha 1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene J. Biol. Chem., June 30, 2000; 275(27): 20837 - 20846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. Anghel, V. Perly, G. Melancon, A. Barsalou, S. Chagnon, A. Rosenauer, W. H. Miller Jr., and S. Mader Aspartate 351 of Estrogen Receptor alpha Is Not Crucial for the Antagonist Activity of Antiestrogens J. Biol. Chem., June 30, 2000; 275(27): 20867 - 20872. [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 |
