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Molecular and Cellular Biology, September 2002, p. 6286-6297, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6286-6297.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Ca2+-Dependent Nuclear Export Mediated by Calreticulin

James M. Holaska,1,2,{dagger} Ben E. Black,1,3,{ddagger} Fraydoon Rastinejad,3,4 and Bryce M. Paschal1,3*

Center for Cell Signaling,1 Departments of Microbiology,2 Biochemistry and Molecular Genetics,3 Pharmacology, University of Virginia, Charlottesville, Virginia 229084

Received 22 January 2002/ Returned for modification 6 March 2002/ Accepted 23 May 2002

We have characterized a pathway for nuclear export of the glucocorticoid receptor (GR) in mammalian cells. This pathway involves the Ca2+ -binding protein calreticulin (CRT), which directly contacts the DNA binding domain (DBD) of GR and facilitates its delivery from the nucleus to the cytoplasm. In the present study, we investigated the role of Ca2+ in CRT-dependent export of GR. We found that removal of Ca2+ from CRT inhibits its capacity to stimulate the nuclear export of GR in digitonin-permeabilized cells and that the inhibition is due to the failure of Ca2+-free CRT to bind the DBD. These effects are reversible, since DBD binding and nuclear export can be restored by Ca2+ addition. Depletion of intracellular Ca2+ inhibits GR export in intact cells under conditions that do not inhibit other nuclear transport pathways, suggesting that there is a Ca2+ requirement for GR export in vivo. We also found that the Ran GTPase is not required for GR export. These data show that the nuclear export pathway used by steroid hormone receptors such as GR is distinct from the Crm1 pathway. We suggest that signaling events that increase Ca2+ could positively regulate CRT and inhibit GR function through nuclear export.

* Corresponding author. Mailing address: Box 800577 Hospital West, Health Sciences System, University of Virginia, Charlottesville, VA 22908. Phone: (434) 243-6521. Fax: (434) 924-1236. E-mail: paschal{at}virginia.edu.

{dagger} Present address: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

{ddagger} Present address: Ludwig Institute for Cancer Research, University of California, San Diego, CA 92093.

Molecular and Cellular Biology, September 2002, p. 6286-6297, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6286-6297.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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