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J. Biol. Chem., Vol. 283, Issue 37, 25576-25588, September 12, 2008

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Thyroid Hormone Receptor 1 Follows a Cooperative CRM1/Calreticulin-mediated Nuclear Export Pathway^*

From the Department of Biology, College of William and Mary, Williamsburg, Virginia 23187

The thyroid hormone receptor 1 (TR) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T₃). Previously, we have shown that TR, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TR is its ability to exit the nucleus through the nuclear pore complex. TR export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TR. We show that, in addition to shuttling in heterokaryons, TR shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TR directly interacts with calreticulin, and point to the intriguing possibility that TR follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TR from the nucleus to cytoplasm.

Received for publication, December 24, 2007 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant 2R15 DK058028-02 and National Science Foundation Grant MCB-0646506 (to L. A. A.). This work was also supported by a Howard Hughes Medical Institute grant through the Undergraduate Biological Sciences Education Program to the College of William & Mary (to N. G. C., L. E. A., and A. P. A.). 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.

¹ Both authors contributed equally to this work.

² Current address: Dept. of Functional Genomics, Imaging Core, Genomic Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA 92121.

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³ To whom correspondence should be addressed: P. O. Box 8795, Millington Hall 116, Williamsburg, VA 23187-8795. Tel.: 757-221-2232; Fax: 757-221-6483; E-mail: laalli{at}wm.edu.

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