Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection

Marshall, Aileen; Rushbrook, Simon; Davies, Susan; Morris, Lydia; Scott, Ian; Vowler, Sarah L.; Coleman, Nicholas; Alexander, Graeme

doi:10.1053/j.gastro.2004.09.076

Cited by 188 publications

(155 citation statements)

References 39 publications

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“…Indeed, the activation of the Ras-Erk pathway by EGF is required for primary hepatocytes to progress through a restriction point in the late G 1 phase (Talarmin et al, 1999). Furthermore, it has been demonstrated recently that liver biopsies from HCV-positive individuals are enriched for cells in the G 1 phase of the cell cycle in comparison with other chronic liver conditions (Marshall et al, 2005), consistent with the effect of HCV NS5A on the Ras-Erk pathway. The observation that GBV-B NS5A is unable to block Ras-Erk signalling suggests that perturbation of this pathway may be important for the establishment of chronic infection.…”

Section: Discussionsupporting

confidence: 69%

A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

Mankouri

Milward

Pryde

et al. 2008

Journal of General Virology

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GB virus B (GBV-B) is the closest relative to hepatitis C virus (HCV) with which it shares a common genome organization, however, unlike HCV in humans, it generally causes an acute resolving hepatitis in New World monkeys. It is important to understand the factors regulating the different disease profiles of the two viruses and in this regard, as well as playing a key role in viral RNA replication, the HCV NS5A non-structural protein modulates a variety of host-cell signalling pathways. We have shown previously that HCV NS5A, expressed either alone, or in the context of the complete polyprotein, inhibits the Ras-extracellular-signal-regulated kinase (Erk) pathway and activates the phosphoinositide 3-kinase (PI3K) pathway. In this report, we investigate whether these functions are shared by GBV-B NS5A. Immunofluorescence analysis revealed that a C-terminally FLAG-tagged GBV-B NS5A exhibited a punctate cytoplasmic distribution. However, unlike HCV NS5A, the GBV-B protein did not partially co-localize with early endosomes. Utilizing a transient luciferase reporter system, we observed that GBV-B NS5A failed to inhibit Ras-Erk signalling, however GBV-B NS5A expression did result in the elevation of b-catenin-dependent transcription via activation of the PI3K pathway. These effects of GBV-B and HCV NS5A on the PI3K and Ras-Erk pathways were confirmed in cells harbouring subgenomic replicons derived from the two viruses. Based on these data we speculate that the differential effects of the two NS5A proteins on cellular signalling pathways may contribute to the differences in the natural history of the two viruses. INTRODUCTIONGB virus B (GBV-B) is the closest phylogenetic relative of hepatitis C virus (HCV) (Muerhoff et al., 1995;Ohba et al., 1996); it shares up to 28 % overall amino acid identity with HCV, rising to 50 % conservation in regions such as the NS3 coding sequence. GBV-B has been proposed as a model for HCV infection and has been used to characterize candidate antivirals as well as for pathogenesis studies (Beames et al., 2001;Bright et al., 2004). It shares the hepatotropism of HCV. Although GBV-B has been reported to lead to persistent infections in some cases in tamarins (Saguinus species) (Martin et al., 2003;Nam et al., 2004), unlike the human virus, GBV-B primarily causes an acute, resolving hepatitis in tamarins and other New World monkeys such as common marmosets (Callithrix jacchus) (Bukh et al., 2001;Jacob et al., 2004;Lanford et al., 2003). In contrast, HCV is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, affecting an estimated 3 % of the world's population.Both GBV-B and HCV are members of the genus Hepacivirus of the family Flaviviridae and have a positivesense RNA genome that is translated in a cap-independent fashion to generate a polyprotein, cleaved by host and viral proteases to produce 10 mature viral proteins. There are three structural proteins at the N terminus: core, E1 and E2, followed by a small cation channel, p7 (p13 in GBV-B). The C-terminal t...

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Section: Discussionsupporting

confidence: 69%

A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

Mankouri

Milward

Pryde

et al. 2008

Journal of General Virology

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“…However, it is pertinent to note that ERK signalling is involved in many processes, such as control of the cell cycle: growth-factor signalling through ERK is required for hepatocytes to transit a block in late G 1 (Talarmin et al, 1999) and many viruses, such as murine coronavirus , human parvovirus B19 (Morita et al, 2003) and Kaposi's sarcomaassociated herpesvirus (Izumiya et al, 2003), have been shown to effect a G 1 block to favour virus replication. Interestingly, a recent study observed elevated levels of G 1 -phase hepatocytes in biopsy material taken from patients with HCV compared with alcoholic liver disease, providing indirect evidence for a G 1 block in HCV infection (Marshall et al, 2005). We propose, therefore, that the inhibition of Ras-ERK signalling by NS5A may play a role in cell-cycle perturbation during HCV infection.…”

Section: Discussionmentioning

confidence: 66%

Perturbation of epidermal growth factor receptor complex formation and Ras signalling in cells harbouring the hepatitis C virus subgenomic replicon

Macdonald

Chan

Harris

2005

Journal of General Virology

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Hepatitis C virus non-structural NS5A protein inhibits epidermal growth factor (EGF)-stimulated activation of the Ras-ERK mitogen-activated protein kinase pathway at a point upstream of Ras activation. To determine the mechanism of this inhibition, the events occurring between the EGF receptor and Ras in Huh-7 cells harbouring the HCV subgenomic replicon were investigated. It was shown that, following EGF stimulation, these cells exhibited decreased EGF receptor tyrosine phosphorylation, aberrant recruitment of the adaptor proteins ShcA and Grb2 to the EGF receptor, reduced phosphorylation of ShcA and reduced Ras activation in comparison with control cells. These data are consistent with effects of NS5A and/or other components of the replicon on multiple events occurring upstream of Ras. INTRODUCTIONHepatitis C virus (HCV) is the leading cause of liver disease and transplantation in the developing world and is estimated to infect 3 % of the global population (WHO, 1999). More than 80 % of those infected will develop a chronic disease culminating in liver fibrosis, cirrhosis and hepatocellular carcinoma. The HCV genome is a 9?5 kb positive-sense RNA molecule that is translated in a capindependent fashion via an internal ribosome entry site to generate a 3000 residue polypeptide, cleaved by host and viral proteases to produce 10 mature viral proteins.The NS5A protein is one of six non-structural proteins that are believed to form a membrane-bound RNA-replication complex . Further to this role, NS5A has been shown to modulate a range of cellular signalling pathways, including the mitogen-activated protein kinase (MAPK) pathways. In particular, we and others have shown that NS5A expression is able to inhibit the Ras-ERK MAPK pathway (Tan et al., 1999;Georgopoulou et al., 2003;Macdonald et al., 2003). This pathway is activated by growth factors binding to their cognate receptors; this induces autophosphorylation of the receptors on tyrosine residues, which then act as ligands for the Src homology 2 (SH2) domains of adaptor proteins, such as ShcA and Grb2. Grb2 associates with a guanine nucleotideexchange factor, Sos, which induces GDP/GTP exchange on the GTP-binding protein Ras (Tari & Lopez-Berestein, 2001). Ras then binds to and activates a serine kinase, Raf, which triggers a kinase cascade ultimately leading to c-Fos expression and concomitant activation of the AP-1 transcription factor (of which c-Fos is a component). We previously demonstrated that transfection of a dominant-active mutant of Ras was able to override the NS5A-mediated block to this pathway and we therefore concluded that NS5A was acting between the epidermal growth factor receptor (EGFR) and the activation of Ras (Macdonald et al., 2003). The mechanism of this inhibition is unknown, although it has been shown that NS5A is able to bind Grb2 (Tan et al., 1999;, By doing so, it is possible that NS5A might inhibit the formation of the Grb2-Sos complex, thereby breaking the link between the activated EGFR and Ras. However, it has previously been sta...

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“…3,45,46 The factors mediating the fate of progenitors after oxidative damage to mature hepatocytes remain poorly understood. To investigate this, we employed two well-accepted mouse models of oxidative liver injury, chronic NASH and acute ethionine-induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, other groups demonstrated that fibrosis correlated with the ductular response to oxidative liver injury in mice with normal leptin genes, 54 and in patients with various types of chronic liver disease. 46,55,56 Hence, participation of epithelial-mesenchymal transitions in hepatic fibrogenesis may not be limited to leptin-deficient mice.…”

Section: Hedgehog Activity and Nash Sv Fleig Et Almentioning

confidence: 99%

Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice

Fleig

Choi

Yang

et al. 2007

Laboratory Investigation

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Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection

Cited by 188 publications

References 39 publications

A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B

Perturbation of epidermal growth factor receptor complex formation and Ras signalling in cells harbouring the hepatitis C virus subgenomic replicon

Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice

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