title: FUSE Binding Protein 1 Facilitates Persistent Hepatitis C Virus Replication in Hepatoma Cells by Regulating Tumor Suppressor p53.
abstract: Hepatitis C virus (HCV) is a leading cause of chronic hepatitis C (CHC), liver cirrhosis, and hepatocellular carcinoma (HCC). Immunohistochemistry of archived HCC tumors showed abundant FBP1 expression in HCC tumors with the CHC background. Oncomine data analysis of normal versus HCC tumors with the CHC background indicated a 4-fold increase in FBP1 expression with a concomitant 2.5-fold decrease in the expression of p53. We found that FBP1 promotes HCV replication by inhibiting p53 and regulating BCCIP and TCTP, which are positive and negative regulators of p53, respectively. The severe inhibition of HCV replication in FBP1-knockdown Huh7.5 cells was restored to a normal level by downregulation of either p53 or BCCIP. Although p53 in Huh7.5 cells is transcriptionally inactive as a result of Y220C mutation, we found that the activation and DNA binding ability of Y220C p53 were strongly suppressed by FBP1 but significantly activated upon knockdown of FBP1. Transient expression of FBP1 in FBP1 knockdown cells fully restored the control phenotype in which the DNA binding ability of p53 was strongly suppressed. Using electrophoretic mobility shift assay (EMSA) and isothermal titration calorimetry (ITC), we found no significant difference in in vitro target DNA binding affinity of recombinant wild-type p53 and its Y220C mutant p53. However, in the presence of recombinant FBP1, the DNA binding ability of p53 is strongly inhibited. We confirmed that FBP1 downregulates BCCIP, p21, and p53 and upregulates TCTP under radiation-induced stress. Since FBP1 is overexpressed in most HCC tumors with an HCV background, it may have a role in promoting persistent virus infection and tumorigenesis.
  
  
  OBJECTIVE
  It is our novel finding that FUSE binding protein 1 (FBP1) strongly inhibits the function of tumor suppressor p53 and is an essential host cell factor required for HCV replication. Oncomine data analysis of a large number of samples has revealed that overexpression of FBP1 in most HCC tumors with chronic hepatitis C is significantly linked with the decreased expression level of p53. The most significant finding is that FBP1 not only physically interacts with p53 and interferes with its binding to the target DNA but also functions as a negative regulator of p53 under cellular stress. FBP1 is barely detectable in normal differentiated cells; its overexpression in HCC tumors with the CHC background suggests that FBP1 has an important role in promoting HCV infection and HCC tumors by suppressing p53.
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Updesh
authors.initials: U
authors.lastname: Dixit
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Neiditch
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Klein
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, New Jersey, USA vnp22@njms.rutgers.edu.
authors.forename: Virendra N
authors.initials: VN
authors.lastname: Pandey
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D011485:Protein Binding; D016601:RNA-Binding Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; D016159:Tumor Suppressor Protein p53; D004265:DNA Helicases