Cell cycle regulation of hepatitis C virus internal ribosomal entry site–directed translation

Honda, Masao; Kaneko, Shuichi; Matsushita, Eiki; Kobayashi, Kenichi; Abell, Geoffrey; Lemon, Stanley M.

doi:10.1016/s0016-5085(00)70424-0

Cited by 141 publications

(119 citation statements)

References 28 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…We have shown that HCV RNA synthesis is stimulated during the S phase of the cell cycle (13). Moreover, compared with capdependent translation, the cap-independent translation of HCV RNA is enhanced in actively growing cells and reduced in resting cells (29). Thus, the stimulus to cell proliferation provided by down-regulation of Rb would be expected to enhance the replication of HCV, whereas increases in Rb expression would have the reverse effect.…”

Section: Discussionmentioning

confidence: 97%

Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase

Munakata

Nakamura

Liang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

135

150

View full text Add to dashboard Cite

The retinoblastoma tumor-suppressor protein (Rb) plays a critical role in controlling cellular proliferation and apoptosis by regulating E2F transcription factors. Rb is a key target of oncoproteins expressed by DNA tumor viruses, but RNA viruses are not known to regulate Rb function. Here, we show that Rb abundance is negatively regulated in cells containing replicating genomic RNA from hepatitis C virus, a human virus strongly associated with hepatocellular carcinoma. The viral RNA-dependent RNA polymerase NS5B forms a complex with Rb, targeting it for degradation and resulting in reduction of Rb abundance, activation of E2F-responsive promoters, and cell proliferation. NS5B contains a conserved Leu-x-Cys͞Asn-x-Asp motif that is homologous to Rb-binding domains in the oncoproteins of DNA viruses. This domain overlaps the polymerase active site, and mutations within it abrogate Rb binding and reverse the effects of NS5B on E2F promoter activation and cell proliferation. These findings suggest a unique link between an oncogenic RNA virus implicated in the development of liver cancer and a critically important tumor-suppressor protein.cell cycle regulation ͉ chronic hepatitis ͉ E2F transcription factor ͉ hepatocellular carcinoma ͉ viral oncogenesis H epatitis C virus (HCV) infection is a leading cause of morbidity and mortality in many human populations (1). Persons with persistent HCV infection are at increased risk of developing cirrhosis and hepatocellular carcinoma (2). The strong association between hepatocellular carcinoma and HCV infection is particularly notable in that HCV is a positive-strand RNA virus, classified within the genus Hepacivirus of the family Flaviviridae. Its 9.6-kb genome replicates exclusively within the cytoplasm (3) and encodes a single, large polyprotein that is processed by cellular and viral proteases into only 10 individual structural and nonstructural viral proteins. Although inflammation associated with chronic hepatitis C is likely to contribute to the development of hepatocellular carcinoma, there is evidence that one or more of the proteins expressed by the virus contribute directly to carcinogenesis. Transgenic mice expressing a high abundance of the core protein develop hepatocellular carcinoma and steatosis (4). Liver cancer also developed in transgenic mice expressing a much lower abundance of the entire viral polyprotein but not in a companion transgenic lineage expressing a higher abundance of the structural proteins (core, E1, E2, and p7) only (5). Such data suggest a direct role for both structural and nonstructural proteins of HCV in oncogenesis.Mechanisms that regulate cell-cycle progression are frequently disrupted in hepatocellular carcinomas associated with HCV infection. These regulatory mechanisms include the retinoblastoma protein (Rb) (6), which plays a major role in controlling the G1 to S-phase transition through a repressive effect on E2F transcription factors (7). Rb functions as a tumor suppressor, and the gene which encodes it (RB) is frequently mutated...

show abstract

Section: Discussionmentioning

confidence: 97%

Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase

Munakata

Nakamura

Liang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

135

150

View full text Add to dashboard Cite

show abstract

“…A complete discussion of the potential implications of these processes for HCV replication would seem overspeculative at this juncture; however, it is interesting to note that the PI3K pathway regulates the activity of the cell translation machinery via the activation of the mammalian target of rapamycin (mTOR) (32) and ribosomal S6 kinase (p70 s6k ) (10). Taken together with the recent observations that activity of the HCV internal ribosome entry site (IRES) is regulated during the cell cycle (33), and expression of NS5A stimulates IRES function (34), it is intriguing to speculate that up-regulation of FIG. 7.…”

Section: Discussionmentioning

confidence: 98%

The Hepatitis C Virus NS5A Protein Activates a Phosphoinositide 3-Kinase-dependent Survival Signaling Cascade

Street¹,

Macdonald

Crowder

et al. 2004

Journal of Biological Chemistry

204

184

View full text Add to dashboard Cite

Hepatitis C virus (HCV) establishes a persistent infection, with up to 80% of infected individuals proceeding to chronic hepatitis, which in many cases may result in liver cirrhosis and hepatocellular carcinoma (HCC); indeed HCV infection is increasingly associated with the development of HCC. The long time period (up to 30 years) between primary infection and the onset of HCC implies that HCV is not directly oncogenic but in some way predisposes patients to develop tumors, though the mechanism for this is unclear as yet. We report here that NS5A binds directly to the Src homology 3 domain of the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K), and this interaction is mediated by a novel (nonproline-rich) motif within NS5A. Coimmunoprecipitation analysis revealed that NS5A bound native heterodimeric PI3K and enhanced the phosphotransferase activity of the catalytic (p110) subunit both in vitro and in human cell lines harboring a subgenomic HCV replicon or expressing NS5A alone. NS5A-mediated activation of PI3K resulted in increased phosphorylation and activity of Akt/protein kinase B and concomitantly provided protection against the induction of apoptosis in both replicon-harboring cells and cells stably expressing NS5A alone. These data suggest that stimulation of PI3K by NS5A may represent an indirect mechanism for development of HCC in HCV-infected patients and further suggests potential therapeutic strategies to counteract the occurrence of HCV-related HCC.

show abstract

“…In vitro evidence suggests that internal ribosome entry site activity is significantly increased in regenerating cells and reduced in quiescent cells. 16 These laboratory phenomena suggest that the significant hepatocyte regeneration that occurs after LDLT may promote HCV replication. Our observation that the incidence of CHC a syndrome associated with significant serum and intrahepatic viral replication 17,18 was significantly more common in LDLT versus CAD may imply that this concept is valid.…”

Section: Discussionmentioning

confidence: 99%

Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors

Gaglio

Malireddy

Levitt

et al. 2003

Liver Transplantation

125

View full text Add to dashboard Cite

Histologic injury caused by recurrent hepatitis C virus (HCV) has been reported in up to 90% of HCV-infected patients who undergo liver transplantation with a cadaveric graft. However, the natural history of HCV after living donor liver transplantation (LDLT) is not well described. We performed a retrospective analysis of 68 consecutive HCV-infected adult patients: 45 recipients of cadaveric grafts (CAD) were compared with 23 LDLT patients. Elevated serum transaminases, positive HCV RNA, and liver biopsy consistent with histologic evidence of HCV defined recurrence. When comparing CAD with LDLT, both the incidence of HCV recurrence and time to recurrence were not different. The overall incidence of severe sequelae of HCV recurrence, either cholestatic hepatitis, grade III-IV inflammation, and/or HCV-induced graft failure requiring retransplantation, was also not different when comparing CAD with LDLT. However, when comparing CAD versus LDLT, no CAD patient developed cholestatic hepatitis C, compared with 17% of LDLT who developed this complication (P ‫؍‬ .001). Thus, in this patient population, the timing and incidence of HCV recurrence were not different when comparing CAD versus LDLT, but the incidence of cholestatic hepatitis was significantly greater in patients with HCV who underwent LDLT. (Liver Transpl 2003;9:1028-1035.) E nd stage liver disease caused by hepatitis C virus (HCV) is the most common indication for liver transplantation in the United States. However, complications caused by recurrent HCV infection are increasingly being recognized; in patients with active HCV replication before transplantation, reacquisition of viremia after transplantation is universal, and allograft hepatitis caused by HCV occurs in up to 90% of patients followed for 5 years. 1-9 Although histologic injury in the allograft caused by HCV is exceedingly common, disease progression after the development of hepatitis is variable, with some patients experiencing indolent disease and others rapidly progressing to cirrhosis and liver failure. In patents who develop HCV-associated cirrhosis posttransplantation, rapid decompensation is a common occurrence. It has been reported that up to 42% of patients with HCV-associated cirrhosis posttransplantation develop decompensation manifested as ascites, encephalopathy, or hepatic hydrothorax, and fewer than 50% of patients survive more than 1 year after the development of decompensation. 10-12 Thus, both prospective and retrospective data are emerging that indicate that the progression of HCV after orthotopic liver transplantation is accelerated when compared with nontransplantation patients. This has been attributed to multiple factors, including the impact of immunosuppression on viral replication and host defenses. 13 Several lines of anecdotal evidence suggest that HCV recurrence might be more severe in recipients of living donor liver transplantation (LDLT). We hypothesize that postoperative liver regeneration in the partial graft procured from living donors may facilitate HCV repli...

show abstract

Cell cycle regulation of hepatitis C virus internal ribosomal entry site–directed translation

Cited by 141 publications

References 28 publications

Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase

Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase

The Hepatitis C Virus NS5A Protein Activates a Phosphoinositide 3-Kinase-dependent Survival Signaling Cascade

Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors

Contact Info

Product

Resources

About