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Molecular and Cellular Biology, February 1999, p. 1025-1037, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Discrimination between NL1- and NL2-Mediated Nuclear Localization of the Glucocorticoid Receptor

Joanne G. A. Savory,1 Brian Hsu,1 Ian R. Laquian,1 Ward Giffin,2 Terry Reich,2 Robert J. G. Haché,2,3,* and Yvonne A. Lefebvre2,3,*

Departments of Medicine2 and Biochemistry, Immunology and Microbiology3 and Graduate Program in Biochemistry,1 The Loeb Health Research Institute at the Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada

Received 16 June 1998/Returned for modification 4 August 1998/Accepted 3 November 1998

Glucocorticoid receptor (GR) cycles between a free liganded form that is localized to the nucleus and a heat shock protein (hsp)-immunophilin-complexed, unliganded form that is usually localized to the cytoplasm but that can also be nuclear. In addition, rapid nucleocytoplasmic exchange or shuttling of the receptor underlies its localization. Nuclear import of liganded GR is mediated through a well-characterized sequence, NL1, adjacent to the receptor DNA binding domain and a second, uncharacterized motif, NL2, that overlaps with the ligand binding domain. In this study we report that rapid nuclear import (half-life [t1/2] of 4 to 6 min) of agonist- and antagonist-treated GR and the localization of unliganded, hsp-associated GRs to the nucleus in G0 are mediated through NL1 and correlate with the binding of GR to pendulin/importin alpha . By contrast, NL2-mediated nuclear transfer of GR occurred more slowly (t1/2 = 45 min to 1 h), was agonist specific, and appeared to be independent of binding to importin alpha . Together, these results suggest that NL2 mediates the nuclear import of GR through an alternative nuclear import pathway. Nuclear export of GR was inhibited by leptomycin B, suggesting that the transfer of GR to the cytoplasm is mediated through the CRM1-dependent pathway. Inhibition of GR nuclear export by leptomycin B enhanced the nuclear localization of both unliganded, wild-type GR and hormone-treated NL1- GR. These results highlight that the subcellular localization of both liganded and unliganded GRs is determined, at least in part, by a flexible equilibrium between the rates of nuclear import and export.

* Corresponding author. Mailing address: The Loeb Health Research Institute, 725 Parkdale Ave., Ottawa, Ontario, Canada K1Y 4E9. Phone: (613) 761-5142. Fax: (613) 761-5036. E-mail for Robert J. G. Haché: rhache{at}lri.ca. E-mail for Yvonne A. Lefebvre: lefebvre{at}civich.ottawa.on.ca.

Molecular and Cellular Biology, February 1999, p. 1025-1037, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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