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J. Biol. Chem., Vol. 280, Issue 48, 40152-40160, December 2, 2005

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Nuclear Import of the Retinoid X Receptor, the Vitamin D Receptor, and Their Mutual Heterodimer^*

Rubina Yasmin, Rebecca M. Williams1, Ming Xu, and Noa Noy2

From the Division of Nutritional Sciences and Departments of Applied and Engineering Physics and Biomedical Sciences, Cornell University, Ithaca, New York 14853

The nuclear receptor retinoid X receptor (RXR) can regulate transcription through homotetramers, homodimers, and heterodimers with other nuclear receptors such as the vitamin D receptor (VDR). The mechanisms that underlie the nuclear import of RXR, VDR, and RXR-VDR heterodimers were investigated. We show that RXR and VDR translocate into the nucleus by distinct pathways. RXR strongly bound to importin and was predominantly nuclear in the absence of ligand. Importin binding and nuclear localization of RXR were modestly enhanced by its ligand, 9-cis-retinoic acid. On the other hand, VDR selectively associated with importin. Importin association and correspondingly nuclear import of VDR were markedly augmented by 1,25(OH)₂D₃. RXR-VDR dimerization inhibited the ability of RXR to bind importin and to mobilize into the nucleus using its own nuclear localization signal. In contrast, VDR recruited RXR-VDR heterodimers to importin and mediated nuclear import of the heterodimers in response to 1,25(OH)₂D₃. Hence nuclear import of RXR-VDR heterodimers is mediated preferentially by VDR and is controlled by the VDR ligand. The observations reveal a novel mechanism by which an RXR heterodimerization partner dominates the activity of the heterodimers.

Received for publication, July 15, 2005 , and in revised form, August 29, 2005.

^* This work was supported in part by National Institutes of Health Grant RO1-CA68150 (to N. N.). 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 Supported by NIBIB/National Center for Research Resources, National Institutes of Health Grant 9 P41 EB001976-16.

² To whom correspondence should be addressed: Division of Nutritional Sciences, 222 Savage Hall, Cornell University, Ithaca, NY 14853. Tel.: 607-255-2490; Fax: 607-255-1033; E-mail: nn14{at}cornell.edu.

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