title: p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3.
abstract: Hepatitis C virus (HCV) NS3 protein is known to affect normal cellular functions, such as cell proliferation and cell death, and to be involved, either directly or indirectly, in HCV hepatocarcinogenesis. In this study, we demonstrated that NS3 protein could specifically repress the promoter activity of p21 in a dose-dependent manner. The effect was not cell type-specific and was synergistic when combined with HCV core protein. Repression of the p21 promoter by NS3 was almost completely lost when p53 binding sites present on the p21 promoter were removed. Furthermore, p53 binding sites were sufficient to confer a strong NS3 responsiveness to an heterologous promoter, suggesting that NS3 represses the transcription of p21 by modulating the activity of p53. Although the NS3 protein domain required for the majority of p21 repression was located on the protease domain, the proteinase activity itself does not seem to be necessary for repression. Both transcription and protein stability of p53 were unaffected by NS3, suggesting that NS3 might repress transcription of p21 by inhibiting the regulatory activity of p53 via protein-protein interaction(s). Finally, the growth rate of NS3-expressing cell lines was at least twice as fast as that of the parent NIH 3T3 cells, indicating that the repression of p21 is actually reflected by the stimulation of cell growth.
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Republic of Korea1.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kwun
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Republic of Korea1.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Jung
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Republic of Korea1.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Ahn
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Republic of Korea1.
authors.forename: Mi Nam
authors.initials: MN
authors.lastname: Lee
authors.affiliation: Department of Microbiology, College of Natural Sciences, Pusan National University, Pusan 609-735, Republic of Korea1.
authors.forename: Kyung Lib
authors.initials: KL
authors.lastname: Jang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000502:physiology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; C493957:Cdkn1a protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases