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J. Biol. Chem., Vol. 278, Issue 39, 37858-37864, September 26, 2003

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Nuclear Export of the Glucocorticoid Receptor Is Accelerated by Cell Fusion-dependent Release of Calreticulin^*

Rhian F. Walther   ¶, Claudia Lamprecht , Andrew Ridsdale , Isabelle Groulx ||, Stephen Lee || **, Yvonne A. Lefebvre   and Robert J. G. Haché    

From the The Ottawa Health Research Institute and the Departments of Medicine and of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1Y 4E9 and the ^||Department of Cellular and Molecular Medicine and the Kidney Research Center, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Nucleocytoplasmic exchange of nuclear hormone receptors is hypothesized to allow for rapid and direct interactions with cytoplasmic signaling factors. In addition to recycling between a naïve, chaperone-associated cytoplasmic complex and a liganded chaperone-free nuclear form, the glucocorticoid receptor (GR) has been observed to shuttle between nucleus and cytoplasm. Nuclear export of GR and other nuclear receptors has been proposed to depend on direct interactions with calreticulin, which is predominantly localized to the lumen of the endoplasmic reticulum. We show that rapid calreticulin-mediated nuclear export of GR is a specific response to transient disruption of the endoplasmic reticulum that occurs during polyethylene glycol-mediated cell fusion. Using live and digitonin-permeabilized cells we demonstrate that, in the absence of cell fusion, GR nuclear export occurs slowly over a period of many hours independent of direct interaction with calreticulin. Our findings temper expectations that nuclear receptors respond rapidly and directly to cytoplasmic signals in the absence of additional regulatory control. These results highlight the importance of verifying findings of nucleocytoplasmic trafficking using techniques in addition to heterokaryon cell fusion.

Received for publication, June 16, 2003 , and in revised form, July 16, 2003.

^* This work was supported in part by a grant from the Canadian Institutes of Health Research (CIHR) (to Y. A. L. and R. J. G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a studentship from the Government of Ontario.

^** A New Investigator of the CIHR.

An Investigator of the CIHR. To whom correspondence should be addressed: The Ottawa Health Research Institute, Hormones, Growth, and Development Program, 725 Parkdale Ave., Ottawa, Ontario K1Y 4E9, Canada. Tel.: 613-798-5555 (ext. 16283); Fax: 613-761-5036; E-mail: rhache{at}ohri.ca.

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