A role for Hsp90 in retinoid receptor signal transduction

SJ Holley and KR Yamamoto

Department of Cellular and Molecular Pharmacology, University of California, San Francisco 94143-0450, USA.

The ubiquitous heat shock protein Hsp90 appears to participate directly in the function of a broad range of cellular signal transduction components, including steroid hormone receptors; however, an evolutionarily related subclass of intracellular receptors, exemplified by the retinoid receptors RAR and RXR, had been inferred from biochemical studies to function independently of Hsp90. To examine this issue genetically, we measured mammalian and avian retinoid receptor activity in a Saccharomyces cerevisiae strain in which the expression of the yeast Hsp90 homologue could be conditionally repressed approximately 20-fold relative to wild type. We tested transcriptional activation by RAR or RXR-RAR, from two types of retinoic acid response elements, triggered by three different agonist ligands. In every condition, we found that activation was severely compromised under conditions of low Hsp90 expression. We showed that the defect was in signal transduction rather than transcription activation per se, and that high affinity hormone binding was abolished in extracts of cells producing low levels of Hsp90. We suggest that Hsp90 may function in at least one step of signal transduction by all members of the intracellular receptor superfamily.

Volume 6, Issue 12, pp. 1833-1842, 12/01/1995
Copyright © 1995 by The American Society for Cell Biology

This article has been cited by other articles:

				A. K. Lovgren, M. Kovarova, and B. H. Koller cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E2 Synthesis Mol. Cell. Biol., June 15, 2007; 27(12): 4416 - 4430. [Abstract] [Full Text] [PDF]

				M. E. Baker Evolution of metamorphosis: role of environment on expression of mutant nuclear receptors and other signal-transduction proteins Integr. Comp. Biol., December 1, 2006; 46(6): 808 - 814. [Abstract] [Full Text] [PDF]

				T. Tanaka, B. L. Dancheck, L. C. Trifiletti, R. E. Birnkrant, B. J. Taylor, S. H. Garfield, U. Thorgeirsson, and L. M. De Luca Altered Localization of Retinoid X Receptor {alpha} Coincides with Loss of Retinoid Responsiveness in Human Breast Cancer MDA-MB-231 Cells Mol. Cell. Biol., May 1, 2004; 24(9): 3972 - 3982. [Abstract] [Full Text] [PDF]

				H. C. Lee, T. Hon, C. Lan, and L. Zhang Structural Environment Dictates the Biological Significance of Heme-Responsive Motifs and the Role of Hsp90 in the Activation of the Heme Activator Protein Hap1 Mol. Cell. Biol., August 15, 2003; 23(16): 5857 - 5866. [Abstract] [Full Text] [PDF]

				W. B. Pratt and D. O. Toft Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery Experimental Biology and Medicine, February 1, 2003; 228(2): 111 - 133. [Abstract] [Full Text] [PDF]

				H. C. Lee, T. Hon, and L. Zhang The Molecular Chaperone Hsp90 Mediates Heme Activation of the Yeast Transcriptional Activator Hap1 J. Biol. Chem., February 22, 2002; 277(9): 7430 - 7437. [Abstract] [Full Text] [PDF]

				R. Nimmanapalli, E. O’Bryan, and K. Bhalla Geldanamycin and Its Analogue 17-Allylamino-17-demethoxygeldanamycin Lowers Bcr-Abl Levels and Induces Apoptosis and Differentiation of Bcr-Abl-positive Human Leukemic Blasts Cancer Res., March 1, 2001; 61(5): 1799 - 1804. [Abstract] [Full Text]

				J. Cheung and D. F. Smith Molecular Chaperone Interactions with Steroid Receptors: an Update Mol. Endocrinol., July 1, 2000; 14(7): 939 - 946. [Full Text]

				W. G. An, T. W. Schulte, and L. M. Neckers The Heat Shock Protein 90 Antagonist Geldanamycin Alters Chaperone Association with p210bcr-abl and v-src Proteins before Their Degradation by the Proteasome Cell Growth Differ., July 1, 2000; 11(7): 355 - 360. [Abstract] [Full Text]

				B. C. Freeman, S. J. Felts, D. O. Toft, and K. R. Yamamoto The p23 molecular chaperones act at a late step in intracellular receptor action to differentially affect ligand efficacies Genes & Dev., February 15, 2000; 14(4): 422 - 434. [Abstract] [Full Text]

				A. Voss, T Thomas, and P Gruss Mice lacking HSP90beta fail to develop a placental labyrinth Development, January 1, 2000; 127(1): 1 - 11. [Abstract] [PDF]

				L. Yue, T. L. Karr, D. F. Nathan, H. Swift, S. Srinivasan, and S. Lindquist Genetic Analysis of Viable Hsp90 Alleles Reveals a Critical Role in Drosophila Spermatogenesis Genetics, March 1, 1999; 151(3): 1065 - 1079. [Abstract] [Full Text]

				Y. Xu, M. A. Singer, and S. Lindquist Maturation of the tyrosine kinase c-src as a kinase and as a substrate depends on the molecular chaperone Hsp90 PNAS, January 5, 1999; 96(1): 109 - 114. [Abstract] [Full Text] [PDF]

				J.-F. Louvion, T. Abbas-Terki, and D. Picard Hsp90 Is Required for Pheromone Signaling in Yeast Mol. Biol. Cell, November 1, 1998; 9(11): 3071 - 3083. [Abstract] [Full Text]

				X.-G. Zhu, J. A. Hanover, G. L. Hager, and S.-y. Cheng Hormone-induced Translocation of Thyroid Hormone Receptors in Living Cells Visualized Using a Receptor Green Fluorescent Protein Chimera J. Biol. Chem., October 16, 1998; 273(42): 27058 - 27063. [Abstract] [Full Text] [PDF]

				S. P. Bohen Genetic and Biochemical Analysis of p23 and Ansamycin Antibiotics in the Function of Hsp90-Dependent Signaling Proteins Mol. Cell. Biol., June 1, 1998; 18(6): 3330 - 3339. [Abstract] [Full Text]

				J. P. Grenert, W. P. Sullivan, P. Fadden, T. A. J. Haystead, J. Clark, E. Mimnaugh, H. Krutzsch, H.-J. Ochel, T. W. Schulte, E. Sausville, et al. The Amino-terminal Domain of Heat Shock Protein 90 (hsp90) That Binds Geldanamycin Is an ATP/ADP Switch Domain That Regulates hsp90 Conformation J. Biol. Chem., September 19, 1997; 272(38): 23843 - 23850. [Abstract] [Full Text] [PDF]

				W. B. Pratt and D. O. Toft Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones Endocr. Rev., June 1, 1997; 18(3): 306 - 360. [Abstract] [Full Text]

				J.-F. Louvion, R. Warth, and D. Picard Two eukaryote-specific regions of Hsp82 are dispensable for its viability and signal transduction functions in yeast PNAS, November 26, 1996; 93(24): 13937 - 13942. [Abstract] [Full Text] [PDF]

				Y. Fang, A. E. Fliss, D. M. Robins, and A. J. Caplan Hsp90 Regulates Androgen Receptor Hormone Binding Affinity in Vivo J. Biol. Chem., November 8, 1996; 271(45): 28697 - 28702. [Abstract] [Full Text] [PDF]

				K. Prufer, A. Racz, G. C. Lin, and J. Barsony Dimerization with Retinoid X Receptors Promotes Nuclear Localization and Subnuclear Targeting of Vitamin D Receptors J. Biol. Chem., December 22, 2000; 275(52): 41114 - 41123. [Abstract] [Full Text] [PDF]