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J. Biol. Chem., Vol. 279, Issue 12, 11719-11726, March 19, 2004

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Hepatitis C Virus Core Functions as a Suppressor of Cyclin-dependent Kinase-activating Kinase and Impairs Cell Cycle Progression^*

Kazuyoshi Ohkawa, Hisashi Ishida, Fumihiko Nakanishi, Atsushi Hosui, Keiji Ueda¶, Tetsuo Takehara, Masatsugu Hori, and Norio Hayashi||

From the Departments of Molecular Therapeutics, Internal Medicine and Therapeutics, and ^¶Microbiology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

We investigated how the hepatitis C virus (HCV) core protein affects the cell cycle profile and cell cycle-related molecules by using the HCV core-expressing stable transfectant. Analysis of the cell cycle profile showed that HCV core impaired G₁ to S transition. The E2F-mediated transcription, phosphorylation of the retinoblastoma protein, and cyclin-dependent kinase (CDK) 4 and CDK2 activities were suppressed in HCV core-expressing cells. The expression levels of G₁ phase-related CDKs/cyclins and various CDK inhibitors were not substantially affected by expression of HCV core. When influences of HCV core on CDK-activating kinase (CAK) were examined, the expression levels of the CAK components, CDK7, cyclin H, and MAT1, were not affected. However, formation of the ternary CAK complex, CAK activity, and the CDK2 level with activating phosphorylation were inhibited by expression of the HCV core. The direct effect of HCV core on CAK was further assessed in the cell-free system by adding the in vitro translated HCV core protein to the anti-CDK7 immunoprecipitate from the cell. The results showed that HCV core led to dissociation of MAT1 from the CAK complex and suppressed the CAK activity. Furthermore, the binding assay revealed that the HCV core was directed against CDK7. Their interaction occurred mainly in the nucleus by the immunostaining. In conclusion, the HCV core protein interacts with CAK and functions as an extrinsic suppressor of CAK. This may be the molecular basis of HCV core-mediated suppression of cell cycle progression. Our findings suggest a novel mechanism concerning HCV core-mediated alteration in the cell cycle machinery.

Received for publication, August 4, 2003 , and in revised form, December 30, 2003.

^* 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: Dept. of Molecular Therapeutics, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3440; Fax: 81-6-6879-3449; E-mail: hayashin{at}moltx.med.osaka-u.ac.jp.

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