Expression of hepatitis C virus non-structural 5A protein in the liver of transgenic mice
| Autor: | Larry P. Thornburg, Xiao Yan Zhou, Ranjit Ray, Robert Steele, Ratna B. Ray, Mainak Majumder, Nancy J. Phillips, Asish K. Ghosh |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Male
Genetically modified mouse Genes Viral Transgene Hepatitis C virus Biophysics Gene Expression Mice Transgenic Viral Nonstructural Proteins Biology medicine.disease_cause Biochemistry Virus Mice 03 medical and health sciences 0302 clinical medicine Structural Biology Interferon Neoplasms Cystitis Genetics medicine Animals Transgenic mice Transgenes STAT3 NS5A Molecular Biology 030304 developmental biology 0303 health sciences Liver Diseases virus diseases Cell Biology medicine.disease Immunohistochemistry Virology digestive system diseases 3. Good health Liver Organ Specificity 030220 oncology & carcinogenesis Hepatocellular carcinoma Carcinogens biology.protein Female NS5A protein Liver specific expression medicine.drug |
| Zdroj: | FEBS Letters. (3):528-532 |
| ISSN: | 0014-5793 |
| DOI: | 10.1016/S0014-5793(03)01337-1 |
| Popis: | Hepatitis C virus (HCV) is a major etiologic agent for chronic hepatitis worldwide often leading to the development of cirrhosis and hepatocellular carcinoma. However, the mechanism for development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. HCV NS5A protein possesses many intriguing properties, including sequestration of p53 in the cytoplasm, downregulation of p21 protein, activation of STAT3, and inhibition of tumor necrosis factor-α-mediated apoptosis. Thus, we investigated whether this viral protein has oncogenic property in vivo. In the absence of an efficient cell culture system for virus growth and a suitable small animal model for HCV infection, transgenic FVB mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter or mouse major urinary promoter (MUP). The apoE promoter is constitutively expressed in liver, on the other hand, the MUP is developmentally regulated and expressed in the liver after birth. Reverse transcription polymerase chain reaction and Western blot analysis indicated establishment of HCV NS5A transgene expression in several lines from both groups of mice. Immunohistochemical studies suggested the presence of NS5A in the cytoplasm of hepatocytes. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a major histological change within the liver up to 24 months of age. Our results suggested HCV NS5A protein is not directly cytopathic or oncogenic in this FVB transgenic mouse model, although this viral protein promotes cell growth in vitro. These animals will be a valuable model of HCV immunopathology as well as for evaluation of siRNA, interferon and other cytokine therapies. |
| Databáze: | OpenAIRE |
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