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Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis.

Authors
 Chul-Yong Park  ;  Soo-Ho Choi  ;  Sang-Min Kang  ;  Ju-Il Kang  ;  Byung-Yoon Ahn  ;  Hoguen Kim  ;  Guhung Jung  ;  Kang-Yell Choi  ;  Soon B. Hwang 
Citation
 JOURNAL OF HEPATOLOGY, Vol.51(5) : 853-864, 2009 
Journal Title
JOURNAL OF HEPATOLOGY
ISSN
 0168-8278 
Issue Date
2009
MeSH
Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; COS Cells ; Carcinoma, Hepatocellular/etiology ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/virology ; Cell Line ; Cell Nucleus/metabolism ; Cercopithecus aethiops ; Cytosol/metabolism ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Hepacivirus/genetics ; Hepacivirus/pathogenicity* ; Hepacivirus/physiology* ; Humans ; In Vitro Techniques ; Liver Neoplasms/etiology* ; Liver Neoplasms/metabolism ; Liver Neoplasms/virology ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Interaction Domains and Motifs ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Replicon ; Sequence Deletion ; Signal Transduction ; Transcription Factor 4 ; Transcription Factors/metabolism ; Transfection ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism* ; Virus Replication ; Wnt Proteins/metabolism ; beta Catenin/chemistry ; beta Catenin/genetics ; beta Catenin/metabolism*
Keywords
Hepatitis C virus ; Liver pathogenesis ; NS5A protein ; β-Catenin signaling ; Tumorigenesis
Abstract
BACKGROUND/AIMS: The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Wnt/beta-catenin signaling has also been involved in tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined the potential effects of HCV NS5A protein on Wnt/beta-catenin signal transduction cascades. METHODS: The effects of NS5A protein on beta-catenin signaling cascades in hepatic cells were investigated by luciferase reporter gene assay, confocal microscopy, immunoprecipitation assay, and immunoblot analysis. RESULTS: beta-Catenin-mediated transcriptional activity is elevated by NS5A protein, in the context of HCV replication, and by infection of cell culture-produced HCV. NS5A protein directly interacts with endogenous beta-catenin and colocalizes with beta-catenin in the cytoplasm. NS5A protein inactivates glycogen synthase kinase 3beta and increases subsequent accumulation of beta-catenin in HepG2 cells. beta-Catenin was also accumulated in HCV patients' liver tissues. In addition, the accumulation of beta-catenin in HCV replicon cells requires both activation of phosphatidylinositol 3-kinase and inactivation of GSK3beta. CONCLUSIONS: NS5A activates beta-catenin signaling cascades through increasing the stability of beta-catenin. This modulation is accomplished by the protein interplay between viral and cellular signaling transducer. These data suggest that NS5A protein may directly be involved in Wnt/beta-catenin-mediated liver pathogenesis.
Full Text
http://www.sciencedirect.com/science/article/pii/S0168827809005273
DOI
10.1016/j.jhep.2009.06.026
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hogeun(김호근)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/105510
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