title: Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus.
abstract: Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN-alpha/beta) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1-STAT2-interferon regulatory factor (IRF)9 trimetric complex called interferon-stimulated gene factor 3 that translocates into the nucleus and binds to the interferon- stimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double-stranded RNA-activated protein kinase (PKR), 2',5'- oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53-knocked-down (p53kd) Huh7 cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh7 cells and p53 was found to directly interact with IRF9.
  
  
  CONCLUSIONS
  These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Narayan
authors.initials: N
authors.lastname: Dharel
authors.forename: Naoya
authors.initials: N
authors.lastname: Kato
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Muroyama
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Amarsanaa
authors.initials: A
authors.lastname: Jazag
authors.forename: Run-Xuan
authors.initials: RX
authors.lastname: Shao
authors.forename: Jin-Hai
authors.initials: JH
authors.lastname: Chang
authors.forename: Mark K
authors.initials: MK
authors.lastname: Adler
authors.forename: Takao
authors.initials: T
authors.lastname: Kawabe
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D002453:Cell Cycle / Q000276:immunology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015870:Gene Expression; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D007372:Interferons / Q000627:therapeutic use; D012093:Replicon / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
chemical_list: C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D007372:Interferons