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J. Biol. Chem., Vol. 279, Issue 15, 14531-14541, April 9, 2004

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Activation of the CKI-CDK-Rb-E2F Pathway in Full Genome Hepatitis C Virus-expressing Cells^*

From the Departments of ^aMicrobiology and Cell Biology and ^hCell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan, the ^cDepartment of Biochemistry, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan, the ^dDivision of Gastroenterology, Showa University Fujigaoka Hospital, Aoba-ku, Fujigaoka 1-30, Yokohama 227-8501, Japan, the ^eFuji Gotemba Research Laboratory, Chugai Pharmaceutical Company, Limited, 135 Komakado 1-chome, Gotemba-shi, Shizuoka 412, Japan, the ^fAIDS Research Center, National Institute of Health, 1-23-1 Toyama-cho, Shinjuku-ku, Tokyo 162-8640, Japan, the ^gDepartment of Chemistry and Biotechnology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, and the ⁱMax-Planck-Institut für Immunbiologie, Stubeweg 51, D-79108 Freiburg, Germany

Hepatitis C virus (HCV) causes persistent infection in hepatocytes, and this infection is, in turn, strongly associated with the development of hepatocellular carcinoma. To clarify the mechanisms underlying these effects, we established a Cre/loxP conditional expression system for the precisely self-trimmed HCV genome in human liver cells. Passage of hepatocytes expressing replicable full-length HCV (HCR6-Rz) RNA caused up-regulation of anchorage-independent growth after 44 days. In contrast, hepatocytes expressing HCV structural, nonstructural, or all viral proteins showed no significant changes after passage for 44 days. Only cells expressing HCR6-Rz passaged for 44 days displayed acceleration of CDK activity, hyperphosphorylation of Rb, and E2F activation. These results demonstrate that full genome HCV expression up-regulates the CDK-Rb-E2F pathway much more effectively than HCV proteins during passage.

Received for publication, November 24, 2003 , and in revised form, January 12, 2004.

^* This work was supported by grant-in-aids from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and from the Ministry of Health, Labor, and Welfare of Japan and by the Organization for Pharmaceutical Safety and Research of Japan. 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.

^b Present address: Lab. Animal Research Center, Inst. of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.

^j To whom correspondence should be addressed. Tel.: 81-3-3823-2101; Fax: 81-3-3828-8945; E-mail: mkohara{at}rinshoken.or.jp.

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