The Amino Terminal Deletion Mutants of Hepatitis C Virus Nonstructural Protein NS5A Function as Transcriptional Activators in Yeast

Tanimoto, Akihide; Ide, Yoshihiro; Arima, Nobuyuki; Sasaguri, Yasuyuki; Padmanabhan, R.

doi:10.1006/bbrc.1997.6967

Cited by 75 publications

(62 citation statements)

References 31 publications

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“…Moreover, cells expressing NS5A exhibited a transformed phenotype and tumor formation in vivo Ghosh et al, 1999). Several studies, including our own, showed that N-terminus-deleted NS5A has a transcriptional activation function (Chung et al, 1997;Kato et al, 1997;Tanimoto et al, 1997;Fukuma et al, 1998). These results suggest that HCV NS5A may act as a transcriptional activator and could play a role in hepatocarcinogenesis.…”

Section: Introductionmentioning

confidence: 59%

“…One possibility for abrogation of the transcriptional transactivation of p53 by N5A may result from a competitive inhibition at the level of transcription factors. We and other groups have showed that the Nterminus-deleted NS5A functions as a transcriptional activator in both yeast and mammalian cells (Chung et al, 1997;Kato et al, 1997;Tanimoto et al, 1997;Fukuma et al, 1998). Several viral activators regulate the transcription of cellular or viral genes through interaction with various components of the basal transcriptional machinery.…”

Section: Discussionmentioning

confidence: 99%

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HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Sheu²,

et al. 2002

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Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis and hepatocellular carcinoma. HCV NS5A, one of non-structural proteins of HCV, was suggested to play a role in oncogenic transformation. Since the tumor suppressor p53 is important for preventing neoplastic transformation, we investigated the functional effects of HCV NS5A on p53. In vitro and in vivo coimmunoprecipitation and confocal microscopy were used to determine the interaction of NS5A and p53. HCV NS5A binds directly to p53 and colocalizes p53 in the perinuclear region. NS5A inhibits transcriptional transactivation by p53 in a dose-dependent manner by use of a reporter assay. Down regulation of endogenous p21/waf1 expression, which is activated by p53 in Hep3B cells, by NS5A was demonstrated by using FLAG-and FLAG-NS5A Hep3B stable cell lines. The effect of NS5A on p53-mediated apoptosis was determined by flow cytometry in both NS5A permanently and transiently transfected Hep3B cells with exogenous p53. The p53-induced apoptosis was abrogated by NS5A and the inhibition effect correlates well with the binding ability of NS5A to p53. In addition, HCV NS5A protein interacts with and colocalizes hTAF II 32, a component of TFIID and an essential coactivator of p53, in vivo. These results suggest that HCV NS5A interacts with and partially sequestrates p53 and hTAF II 32 in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Sheu²,

et al. 2002

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“…Amino-terminal NS5A-Gal4 fusion proteins have trans-activating properties (Tanimoto et al, 1997). Although intact NS5A is cytoplasmic and membrane-bound (Brass et al, 2002), caspase-mediated cleavage exposes a cryptic nuclear localization signal (Ide et al, 1996) and leads to NS5A nuclear localization, where it functions as a PKAregulated transcription factor (Satoh et al, 2000b;Goh et al, 2001).…”

Section: Ns5amentioning

confidence: 99%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type b-catenin and the Wnt-b-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/b-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

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“…Both NS5A and nonstructural protein 5B bind to different domains of a human vesicle-associated membrane protein-associated protein of 33 kDa (hVAP-33) (15), suggesting that NS5A may form part of the HCV RNA replication complex. It has been reported that N terminustruncated NS5A, but not full-length NS5A, is a potent transcriptional activator in yeast and mammalian cells (16,17). Subsequent studies demonstrated that both N-and C-terminal cleaved NS5A product was localized in the nucleus and showed transcriptional activity in the presence of ␣-catalytic subunit of protein kinase A (18).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Nonstructural 5A Protein of Hepatitis C Virus Modulates Tumor Necrosis Factor α-stimulated Nuclear Factor κB Activation

Park

Choi

Lee

et al. 2002

Journal of Biological Chemistry

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The hepatitis C virus nonstructural protein 5A (NS5A) is a multifunctional phosphoprotein that leads to pleiotropic responses, in part by regulating cell growth and cellular signaling pathways. Here we show that overexpression of NS5A inhibits tumor necrosis factor (TNF)-␣-induced nuclear factor B (NF-B) activation in HEK293 cells, as determined by luciferase reporter gene expression and by electrophoretic mobility shift assay. When overexpressed, NS5A cannot inhibit the recruitment of TNF receptor-associated factor 2 (TRAF2) and IB kinase (IKK)␤ into the TNF receptor 1-TNF receptor-associated death domain complex. In contrast, NS5A is a part of the TNF receptor 1 signaling complex. NF-B activation by TNF receptor-associated death domain and TRAF2 was inhibited by NS5A, whereas MEKK1 and IKK␤-dependent NF-B activation was not affected, suggesting that NS5A may inhibit NF-B activation signaled by TRAF2. Coimmunoprecipitation and colocalization of NS5A and TRAF2 expressed in vivo provide compelling evidence that NS5A directly interacts with TRAF2. This interaction was mapped to the middle onethird (amino acids 148 -301) of NS5A and the TRAF domain of TRAF2. Our findings suggest a possible molecular mechanism that could explain the ability of NS5A to negatively regulate TNF-␣-induced NF-B activation.

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The Amino Terminal Deletion Mutants of Hepatitis C Virus Nonstructural Protein NS5A Function as Transcriptional Activators in Yeast

Cited by 75 publications

References 31 publications

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Viral hepatitis and liver cancer: the case of hepatitis C

Nonstructural 5A Protein of Hepatitis C Virus Modulates Tumor Necrosis Factor α-stimulated Nuclear Factor κB Activation

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