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J. Biol. Chem., Vol. 280, Issue 49, 40901-40908, December 9, 2005

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Importin 4 Is Responsible for Ligand-independent Nuclear Translocation of Vitamin D Receptor^*

Yoshiteru Miyauchi, Toshimi Michigami1, Naoko Sakaguchi, Toshihiro Sekimoto¶, Yoshihiro Yoneda¶, John Wesley Pike||, Masayo Yamagata2, and Keiichi Ozono2

From the Department of Environmental Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan, the Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan, the ^¶Department of Frontier Biosciences, Osaka University Graduate School of Frontier Biosciences, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan, and the ^||Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706-1544

Vitamin D receptor (VDR) is localized in nuclei and acts as a ligand-dependent transcription factor. To clarify the molecular mechanisms underlying the nuclear translocation of VDR, we utilized an in vitro nuclear transport assay using digitonin-permeabilized semi-intact cells. In this assay, recombinant whole VDR-(4-427) and a truncated mutant VDR-(4-232) lacking the carboxyl terminus of VDR were imported to nuclei even in the absence of ligand. In contrast, VDR-(91-427) lacking the amino-terminal DNA-binding domain was not imported to nuclei in the absence of ligand, and was efficiently imported in its liganded form. These results suggested that there are two distinct mechanisms underlying the nuclear transport of VDR; ligand-dependent and -independent pathways, and that the different regions of VDR are responsible for these processes. Therefore, we performed the yeast two-hybrid screening using VDR-(4-232) as the bait to explore the molecules responsible for ligand-independent nuclear translocation of VDR, and have identified importin 4 as an interacting protein. In the reconstruction experiments where transport factors were applied as recombinant proteins, recombinant importin 4 facilitated nuclear translocation of VDR regardless of its ligand, whereas importin failed in transporting VDR even in the presence of ligand. In conclusion, importin 4, not importin , is responsible for the ligand-independent nuclear translocation of VDR.

Received for publication, August 24, 2005

^* This work was supported in part by a grant from the Ministry of Health, Labor and Welfare of Japan (to K. O.) and the 21st Century COE entitled "Origination of the Frontier BioDentistry" at Osaka University Graduate School of Dentistry supported by the Ministry of Education, Culture, Sports, Science and Technology (to T. M.). 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.

² A research fellow of the Japan Society for the Promotion of Science.

¹ To whom correspondence should be addressed. Tel.: 81-725-56-1220; Fax: 81-725-57-3021; E-mail: michigami{at}mch.pref.Osaka.jp.

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