| Budget Amount *help |
¥3,870,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
The aim of this study is to investigate the effects of hepatitis C virus (HCV) proteins on protein-tyrosine phosphorylation, in particular, protein-tyrosine kinase Syk in vivo.
In 2006, we identified that HCV non-structural protein 5A (NS5A) strongly interacted with Syk, and phospholipase C (PLC)-γ1 was the intracellular target of Syk in cultured liver cells (Huh-7 cells). Moreover, we investigated the pathological mechanism of HCV NS3 and NS4A, identification of novel SSPE virus, and characterization of virus-related ubiquitin ligase, and reported their results.
In 2007, we found that interaction of NS5A with Syk was detected also in Huh-7.5 cells harboring an HCV RNA replicon and those infected with HCV (HCV J6/JFH-1). Deletion mutational analysis revealed that an N-terminal portion of NS5A was involved in the physical interaction with Syk. In vitro kinase assay demonstrated that NS5A inhibited enzymatic activity of Syk and that, in addition to the N-terminal 175 residues, a central portion of NS5A was required for the Syk inhibition. Moreover, immunohistochemical analysis revealed that endogenous Syk, which otherwise was expressed diffusely in the cytoplasm of normal hepatocytes, was localized near the cell membrane with a patched pattern in HCV-infected hepatocytes. Our results imply the possibility that NS5A is involved in the carcinogenesis of hepatocytes through the suppression of Syk, a potent tumor suppressor in human breast carcinoma. Furthermore, we investigated the pathogenesis of diabetes as a HCV complication and proteome analysis of HCV infection. Furthermore, we examined the role of novel adaptor protein 3BP2 and human inherited disease cherubism and published a review article.
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