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J. Biol. Chem., Vol. 279, Issue 18, 18926-18934, April 30, 2004

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The RING Finger Protein, RNF8, Interacts with Retinoid X Receptor and Enhances Its Transcription-stimulating Activity^*

Yukihiko Takano, Seiji Adachi, Masataka Okuno, Yoshinori Muto¶, Takashi Yoshioka, Rie Matsushima-Nishiwaki, Hisashi Tsurumi, Kenichi Ito||, Scott L. Friedman**, Hisataka Moriwaki, Soichi Kojima, and Yukio Okano

From the Department of Molecular Pathobiochemistry, First Department of Internal Medicine, and ^¶Department of Basic Health Science and Fundamental Nursing, Gifu University School of Medicine, Gifu 500-8705, Japan, ^||Ichimaru Pharcos Company Limited, Gifu 501-0475, Japan, ^**Division of Liver Diseases, Mount Sinai Medical Center, New York, New York 10029-6574, and Molecular Cellular Pathology Research Unit, RIKEN, Wako 351-0198, Japan

Retinoid X receptor (RXR) is a member of the steroid hormone receptor superfamily. Using yeast two-hybrid screening, -galactosidase assays, and pull-down assays, we show that RNF8, a RING finger protein recently isolated as a protein binding to a ubiquitin-conjugating enzyme, binds to RXR through the N-terminal regions of both proteins. In COS7 cells, overexpressed RNF8 colocalized and interacted with RXR in the nucleus, as shown by fluorescence resonance energy transfer. A point mutation of RNF8, Cys-403 to Ser (C403S), which disrupts the RING finger structure, or deletion of the N-terminal region (N) of RNF8 prevented localization of RNF8 to the nucleus without affecting nuclear localization of RXR. Although transient overexpression of RNF8 had little effect on RXR ubiquitination, RNF8 dose-dependently enhanced RXR-mediated transactivation of the RXR-responsive element (RXRE)-bearing gene promoter without the addition of its ligand, 9-cis-retinoic acid (RA), and up-regulated the expression of the genes downstream of RXRE as well as an RA-response element. This transactivation-enhancing activity was not seen with either the C403S point mutant or the N deletion mutant of RNF8. These results suggest a novel function of RNF8 as a regulator of RXR-mediated transcriptional activity through interaction between their respective N-terminal regions.

Received for publication, August 18, 2003 , and in revised form, February 17, 2004.

^* This study was supported in part by grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan (to M. O., H. M., S. K., and Y. O.), NIDDK, National Institutes of Health Grant DK37340 (to S. L. F.), and a Chemical Biology Research Project grant from RIKEN (to S. K.). 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.

To whom correspondence should be addressed. Tel.: 81-58-267-2367; Fax: 81-58-267-2950; E-mail:bunbyo{at}cc.gifu-u.ac.jp.

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