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PNAS 101 (9): 2876-2881

Copyright © 2004 by the National Academy of Sciences.

Cell Biology

Molecular chaperones function as steroid receptor nuclear mobility factors

Cem Elbi *, Dawn A. Walker *, Guillermo Romero {dagger}, William P. Sullivan {ddagger}, David O. Toft {ddagger}, Gordon L. Hager * §, and Donald B. DeFranco {dagger} §

*Laboratory of Receptor Biology and Gene Expression, Building 41, Room B602, National Cancer Institute, Bethesda, MD 20892-5055; {dagger}Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and {ddagger}Department of Biochemistry and Molecular Biology, Mayo Graduate School, Rochester, MN 55905

Communicated by Jack Gorski, University of Wisconsin, Madison, WI, January 8, 2004

Received for publication November 20, 2003.

Abstract: Live cell imaging has revealed the rapid mobility of steroid hormone receptors within nuclei and their dynamic exchange at transcriptionally active target sites. Although a number of other proteins have been shown to be highly mobile within nuclei, the identity of soluble factors responsible for orchestrating nuclear trafficking remains unknown. We have developed a previously undescribed in situ subnuclear trafficking assay that generates transcriptionally active nuclei, which are depleted of soluble factors required for the nuclear mobility of glucocorticoid (GR) and progesterone receptors (PR). Using this system and a fluorescence recovery after photobleaching technique, we demonstrate that nuclear mobility of GR recovered on incubation with reticulocyte lysate was inhibited by geldanamycin, a drug that blocks the chaperone activity of heat-shock protein 90. Direct proof of molecular chaperone involvement in steroid receptor subnuclear trafficking was provided by the ATP-dependent recovery of nuclear mobility of GR and PR on incubation with various combinations of purified chaperone and/or cochaperone proteins. Additionally, for both receptors, the inclusion of hormone during the recovery period leads to a retardation of nuclear mobility. Thus, our results provide a description of soluble nuclear mobility factors and furthermore demonstrate a previously unrecognized role for molecular chaperones in the regulation of steroid receptor function within the nucleus.

Abbreviations: GR, glucocorticoid receptor; PR, progesterone receptor; FRAP, fluorescence recovery after photobleaching; GA, geldanamycin; BrUTP, 5-bromo-UTP; t1/2, half-maximal recovery time.

§ To whom correspondence may be addressed. E-mail: hagerg{at}exchange.nih.gov or dod1{at}pitt.edu.

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