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Journal of Virology, September 2000, p. 8744-8750, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Activation of the Interferon-Inducible 2'-5'-Oligoadenylate Synthetase Gene by Hepatitis C Virus Core Protein

Atsushi Naganuma,1,2,3 Akito Nozaki,1 Torahiko Tanaka,1 Kazuo Sugiyama,1 Hitoshi Takagi,3 Masatomo Mori,3 Kunitada Shimotohno,4 and Nobuyuki Kato1,2,*

Virology and Glycobiology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045,1 Department of Molecular Biology, Institute of Cellular and Molecular Biology, Okayama University School of Medicine, Okayama 700-8558,2 The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511,3 and Laboratory of Human Tumor Viruses, Department of Viral Oncology, The Institute for Virus Research, Kyoto University, Kyoto 606-8937,4 Japan

Received 3 February 2000/Accepted 23 June 2000

The effects of hepatitis C virus (HCV) proteins on several signal transduction pathways in human nonneoplastic hepatocyte PH5CH8 cells were investigated using expression vectors encoding HCV proteins derived from HCV-infected human nonneoplastic cultured T-lymphocyte and hepatocyte cells (MT-2C and PH5CH7), which could support HCV replication. The amino acid sequences of HCV proteins obtained from HCV-infected human cells were identical or very close to the consensus sequences of the proteins derived from the original inoculum used for HCV infection. During the course of the study, we found that HCV core protein specifically activated the 40/46-kDa 2'-5'-oligoadenylate synthetase (2'-5'-OAS) gene promoter in a dose-dependent manner in different human hepatocyte cell lines (PH5CH8, HepG2, and PLC/PRF/5). We also found that the activation by core protein was further enhanced in the cells treated with alpha interferon. The expression of E1 or E2 envelope protein or nonstructural NS5A protein did not activate the 2'-5'-OAS gene promoter. We demonstrated that the activation by core protein in the hepatocyte cells was suppressed by antisense RNA complementary to core-encoding RNA. Deletion mutant analysis of core protein and deletion analysis of the 2'-5'-OAS gene promoter have been performed. Finally, we demonstrated that the activation of the 2'-5'-OAS gene occurred at the transcriptional level and furthermore demonstrated that the endogenous 2'-5'-OAS gene was also activated by core protein. This is the first report to show that a viral protein activated the 2'-5'-OAS gene.

* Corresponding author. Mailing address: Department of Molecular Biology, Institute of Cellular and Molecular Biology, Okayama University Medical School, Shikata-cho, 2-5-1, Okayama 700-8558, Japan. Phone: 81-86-235-7385. Fax: 81-86-235-7392. E-mail: nkato{at}med.okayama-u.ac.jp.

Journal of Virology, September 2000, p. 8744-8750, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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