title: Effect of interferon alpha and cell cycle progression on translation mediated by the hepatitis C virus 5' untranslated region: a study using a transgenic mouse model.
abstract: The effect of interferon alpha (IFN alpha) and the progression of the cell cycle on translation mediated by the 5' untranslated region (5'UTR) of hepatitis C virus (HCV) was evaluated in a transgenic mouse model containing the beta-galactosidase (beta-gal) gene under the control of the mouse albumin promoter and HCV 5'UTR. The transgene was exclusively expressed in the liver and specifically in hepatocytes around the periportal area. IFN alpha significantly suppressed the expression of both the beta-gal gene product and its enzymatic activity at 6 h after the treatment of the mice. The mRNA level of the transgene and endogenous albumin gene expression were not affected, so this suppression was considered to be specific to 5'UTR-directed translation. Phosphorylation of the Stat1 protein was observed in the liver extract 20 min after the treatment, thus confirming a specific known effect of IFN alpha in vivo. We suggest that suppression of 5'UTR-directed translation may be one of the mechanisms whereby IFN alpha exerts its anti-viral activity. We further investigated whether the restriction of 5'UTR-directed translation in periportal hepatocytes may be explained by the proliferative state of the cell. Transgene expression was slightly enhanced in the liver 48 h after partial hepatectomy when a substantial number of hepatocytes entered cell cycle progression. However, 5'UTR-directed translation could not be detected in hepatocellular carcinoma lesions in transgenic mice that were induced to develop such tumours. We suggest that the state of differentiation of the cell, and not its proliferative capacity, is important for supporting HCV expression. This animal model may be a useful tool to dissect the control of HCV expression and to search for ways to block viral replication.
authors.affiliation: The Third Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: S
authors.initials: S
authors.lastname: Okoshi
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Yano
authors.forename: J D
authors.initials: JD
authors.lastname: Gangemi
authors.forename: G
authors.initials: G
authors.lastname: Jay
authors.forename: H
authors.initials: H
authors.lastname: Asakura
authors.forename: Y
authors.initials: Y
authors.lastname: Aoyagi
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000821:virology; D002453:Cell Cycle / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D016174:Hepacivirus / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D007370:Interferon Type I / Q000494:pharmacology*; D007763:Lac Operon; D008113:Liver Neoplasms / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D012709:Serum Albumin / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D012367:RNA, Viral; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D012709:Serum Albumin; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D001616:beta-Galactosidase