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J. Biol. Chem., Vol. 282, Issue 45, 32765-32772, November 9, 2007

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Anti-hepatitis C Virus Activity of Tamoxifen Reveals the Functional Association of Estrogen Receptor with Viral RNA Polymerase NS5B^*

From the Department of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Hepatitis C virus (HCV) is a major causative agent of hepatocellular carcinoma. HCV genome replication occurs in the replication complex (RC) around the endoplasmic reticulum membrane. However, the mechanisms regulating the HCV RC remain widely unknown. Here, we used a chemical biology approach to show that estrogen receptor (ESR) is functionally associated with HCV replication. We found that tamoxifen suppressed HCV genome replication. Part of ESR resided on the endoplasmic reticulum membranes and interacted with HCV RNA polymerase NS5B. RNA interference-mediated knockdown of endogenous ESR reduced HCV replication. Mechanistic analysis suggested that ESR promoted NS5B association with the RC and that tamoxifen abrogated NS5B-RC association. Thus, ESR regulated the presence of NS5B in the RC and stimulated HCV replication. Moreover, the ability of ESR to regulate NS5B was suggested to serve as a potential novel target for anti-HCV therapeutics.

Received for publication, May 30, 2007 , and in revised form, August 15, 2007.

^* This work was supported by grants-in-aid for cancer research and for the second term comprehensive 10-year strategies for cancer control from the Ministry of Health, Labor, and Welfare; by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology; by grants-in-aid for the Research for the Future Program from the Japanese Society for the Promotion of Science; and by grants-in-aid for the Program for Promotion of Fundamental Studies in Health Science from the Organization for Pharmaceutical Safety. 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 To whom correspondence should be addressed: Dept. of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-4000; Fax: 81-75-751-3998; E-mail: kshimoto{at}virus.kyoto-u.ac.jp.

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