Chronic infection by hepatitis C virus (HCV), which is the leading cause of severe hepatitis, often develops into liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms underlying HCV replication and pathogenesis are poorly understood. We have recently identified a cellular factor, FUSE binding protein (FBP) that specifically interacts with HCV 3'NTR and stimulates HCV replication. FBP is known to interact with the pyrimidine-rich far-upstream element (FUSE) of the c-myc proto-oncogene and activate c-myc transcription. C-myc targets approximately 10% of transcribed genes and coordinates many essential cellular processes, including proliferation, growth, and differentiation. C-myc also is consistently elevated in chronically HCV-infected cells, as well as in cells affected by LC and HCC. Our preliminary results have indicated that FBP is overexpressed in HCC with a history of chronic hepatitis C (CHC) but conspicuously absent in other HCC without CHC history. We propose to investigate the mechanisms whereby FPB acts in HCV replication and it possible role in HCV associated pathogenesis.

Public Health Relevance

The major purpose of this proposal is to elucidate the mechanism of FUSE binding protein (FBP)- mediated stimulation of HCV replication and its implication on HC associated pathogenesis. These studies will help delineate how HCV-FBP interactions affect patients infected with HCV, and to determine whether any of these interactions represent targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK083560-01A1
Application #
7788343
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2010-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$195,000
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Biochemistry
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Mishra, Priya; Dixit, Updesh; Pandey, Ashutosh K et al. (2017) Modulation of HCV replication and translation by ErbB3 binding protein1 isoforms. Virology 500:35-49
Dixit, Updesh; Pandey, Ashutosh K; Mishra, Priya et al. (2016) Staufen1 promotes HCV replication by inhibiting protein kinase R and transporting viral RNA to the site of translation and replication in the cells. Nucleic Acids Res 44:5271-87
Dixit, Updesh; Pandey, Ashutosh K; Liu, Zhihe et al. (2015) FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53. J Virol 89:7905-21
Dixit, Updesh; Liu, Zhihe; Pandey, Ashutosh K et al. (2014) Fuse binding protein antagonizes the transcription activity of tumor suppressor protein p53. BMC Cancer 14:925
Manvar, Dinesh; Singh, Kamlendra; Pandey, Virendra N (2013) Affinity labeling of hepatitis C virus replicase with a nucleotide analogue: identification of binding site. Biochemistry 52:432-44
Upadhyay, Alok; Dixit, Updesh; Manvar, Dinesh et al. (2013) Affinity capture and identification of host cell factors associated with hepatitis C virus (+) strand subgenomic RNA. Mol Cell Proteomics 12:1539-52
Manvar, Dinesh; Mishra, Mahesh; Kumar, Suriender et al. (2012) Identification and evaluation of anti hepatitis C virus phytochemicals from Eclipta alba. J Ethnopharmacol 144:545-54