p53-dependent transcriptional repression of p21waf1 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 proteinprotein 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.

The effects of hepatitis C virus non-structural protein 3 on cell growth mediated by extracellular signal-related kinase cascades in human hepatocytes in vitro

“…The proliferative advantage appears in the immortally normal hepatocyte QSG7701 cells expressing stably HCV NS3 protein, suggesting the potential role of HCV NS3 protein in the promotion of cell growth. The results provide an insight into the mechanisms of how the HCV NS3 protein mediates its oncogenic activity in infected cells and are supported by previous findings (14,16,17). In addition, we also show the HCV NS3-stimulated cell growth is ERK/AP-1 cascade dependent.…”

Platelet-derived Growth Factor (PDGF) Receptor-α-activated c-Jun NH2-terminal Kinase-1 Is Critical for PDGF-induced p21 Promoter Activity Independent of p53

“…Among these p21 WAF1/CIP1 transcription regulatory elements are two p53-responsive elements located between nucleotides Ϫ2282 to Ϫ2263 and Ϫ1391 to Ϫ1361, which mediate radiation and viral infection-induced and -suppressed p21 WAF1/CIP1 transcription (30,51), respectively. The GC-rich Sp1 (a transcription factor)-binding elements (52) between nucleotides Ϫ110 and Ϫ65 were shown to mediate transforming growth factor-␤-induced human keratinocyte cell growth arrest (48).…”

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

“…Interestingly, this may also be the case for HCV. Previous studies indicate that of 10 viral proteins encoded by the HCV genome, HCV core protein, and nonstructural protein NS3 and NS5A physically interact with p53, albeit their effects on p53 transcriptional activity vary and are not conclusive yet (Ishido and Hotta, 1998;Ray et al, 1998;Lu et al, 1999;Otsuka et al, 2000;Arima et al, 2001;Kwun et al, 2001;Majumder et al, 2001). In the case of HCV core protein, the evidence of in vivo association and cellular localization is not available.…”