| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Institut National de la Santé et de la Recherche Médicale U33 Lab Hormones 94276 Le Kremlin Bicêtre Cedex, France
The in vivo interaction of estrogen receptor (ER) and Hsp90, demonstrated in the absence of hormone by a nuclear cotranslocation assay of the cytoplasmic Hsp90 with the karyophilic receptor, was disrupted by agonist and antagonist ligands, which, after dissociating the Hsp90, allowed the chaperone protein to be relocalized in the cytoplasm. The pure antiestrogen RU 58668 (RU), which was unable to stimulate an estrogen-dependent reporter gene and completely inhibited its estradiol-induced activity, also profoundly modified the subcellular distribution of ER in a specific time- and dose-dependent manner; ER appeared as speckled fluorescent clusters mainly located in the perinuclear region of the cytoplasm. The kinetics of appearance and reversal of the RU-dependent ER mislocalization in the presence or absence of cycloheximide demonstrated 1) that this effect was reversed by RU withdrawal or estradiol (E2) treatment, and 2) that cycloheximide with RU inhibited and reversed the ER cytoplasmic mislocalization induced by RU alone. These results point to a protein synthesis-dependent step in the mechanism of action of this antiestrogen. After RU treatment, a large portion of ER was found in the particulate fraction of the cytoplasm. However, confocal and electron microscopic analysis showed that ER clusters were not associated with specific cytoplasmic organelles or compartments. Using ER mutants, it was found that the ligand binding domain was sufficient for RU to produce receptor mislocalization, while the constitutive nuclear localization signals were dispensable. We propose that the antiestrogenic properties of RU are primarily due to the induction of an aggregation-prone receptor conformation that cannot undertake the constitutive and the ligand-induced nuclear localization function of the receptor because it is sequestered in the cytoplasm by fast turning over protein(s). We predict that antiestrogens able to block ER nuclear localization will behave as pure antihormones and will inhibit all the nuclear action of ER elicited by agonistic ligands or by ligand-independent mechanisms such as growth factor stimulation.
This article has been cited by other articles:
 |
|
 |
|
  N. B. Berry, M. Fan, and K. P. Nephew Estrogen Receptor-{alpha} Hinge-Region Lysines 302 and 303 Regulate Receptor Degradation by the Proteasome Mol. Endocrinol., July 1, 2008; 22(7): 1535 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng, C. Zhang, and D. J. Shapiro A Functional Serine 118 Phosphorylation Site in Estrogen Receptor-{alpha} Is Required for Down-Regulation of Gene Expression by 17{beta}-Estradiol and 4-Hydroxytamoxifen Endocrinology, October 1, 2007; 148(10): 4634 - 4641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nonclercq, F. Journe, I. Laios, C. Chaboteaux, R.-A. Toillon, G. Leclercq, and G. Laurent Effect of nuclear export inhibition on estrogen receptor regulation in breast cancer cells J. Mol. Endocrinol., August 1, 2007; 39(2): 105 - 118. [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]
|
|
|
|
|
|
M. H. Al-Dhaheri and B. G. Rowan Protein Kinase A Exhibits Selective Modulation of Estradiol-Dependent Transcription in Breast Cancer Cells that Is Associated with Decreased Ligand Binding, Altered Estrogen Receptor {alpha} Promoter Interaction, and Changes in Receptor Phosphorylation Mol. Endocrinol., February 1, 2007; 21(2): 439 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Dahlman-Wright, V. Cavailles, S. A. Fuqua, V. C. Jordan, J. A. Katzenellenbogen, K. S. Korach, A. Maggi, M. Muramatsu, M. G. Parker, and J.-A. Gustafsson International Union of Pharmacology. LXIV. Estrogen Receptors Pharmacol. Rev., December 1, 2006; 58(4): 773 - 781. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Acconcia, B. Manavathi, J. Mascarenhas, A. H. Talukder, G. Mills, and R. Kumar An Inherent Role of Integrin-Linked Kinase-Estrogen Receptor {alpha} Interaction in Cell Migration. Cancer Res., November 15, 2006; 66(22): 11030 - 11038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Long and K. P. Nephew Fulvestrant (ICI 182,780)-dependent Interacting Proteins Mediate Immobilization and Degradation of Estrogen Receptor-{alpha} J. Biol. Chem., April 7, 2006; 281(14): 9607 - 9615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lipfert, J. E. Fisher, N. Wei, A. Scafonas, Q. Su, J. Yudkovitz, F. Chen, S. Warrier, E. T. Birzin, S. Kim, et al. Antagonist-Induced, Activation Function-2-Independent Estrogen Receptor {alpha} Phosphorylation Mol. Endocrinol., March 1, 2006; 20(3): 516 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fan, A. Park, and K. P. Nephew CHIP (Carboxyl Terminus of Hsc70-Interacting Protein) Promotes Basal and Geldanamycin-Induced Degradation of Estrogen Receptor-{alpha} Mol. Endocrinol., December 1, 2005; 19(12): 2901 - 2914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Marsaud, A. Gougelet, S. Maillard, and J.-M. Renoir Various Phosphorylation Pathways, Depending on Agonist and Antagonist Binding to Endogenous Estrogen Receptor {alpha} (ER{alpha}), Differentially Affect ER{alpha} Extractability, Proteasome-Mediated Stability, and Transcriptional Activity in Human Breast Cancer Cells Mol. Endocrinol., October 1, 2003; 17(10): 2013 - 2027. [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]
|
|
|
|
 |
|
 C. M. Klinge Estrogen receptor interaction with estrogen response elements Nucleic Acids Res., July 15, 2001; 29(14): 2905 - 2919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. S. Russell, M. P. Haynes, T. Caulin-Glaser, J. Rosneck, W. C. Sessa, and J. R. Bender Estrogen Stimulates Heat Shock Protein 90 Binding to Endothelial Nitric Oxide Synthase in Human Vascular Endothelial Cells. EFFECTS ON CALCIUM SENSITIVITY AND NO RELEASE J. Biol. Chem., February 18, 2000; 275(7): 5026 - 5030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ozono, M. Saito, D. Miura, T. Michigami, S. Nakajima, and S. Ishizuka Analysis of the Molecular Mechanism for the Antagonistic Action of a Novel 1alpha ,25-Dihydroxyvitamin D3 Analogue toward Vitamin D Receptor Function J. Biol. Chem., November 5, 1999; 274(45): 32376 - 32381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. I. Kang, X. Meng, J. Devin-Leclerc, I. Bouhouche, A. Chadli, F. Cadepond, E.-E. Baulieu, and M.-G. Catelli The molecular chaperone Hsp90 can negatively regulate the activity of a glucocorticosteroid-dependent promoter PNAS, February 16, 1999; 96(4): 1439 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| 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 |
