Activation of nuclear factor ?B in hepatitis C virus infection: Implications for pathogenesis and hepatocarcinogenesis

Tai, Dar‐In; Tsai, Shau‐Wei; Chen, Young-Mao; Chuang, Yen-Ling; Peng, Cheng‐Yuan; Sheen, I‐Shyan; Yeh, Chau‐Ting; Chang, Kenneth S. S.; Huang, Shao-Nan; Kuo, George; Liaw, Yun–Fan

doi:10.1002/hep.510310316

Cited by 180 publications

(130 citation statements)

References 73 publications

(61 reference statements)

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“…The effects of HIV-encoded proteins Tat, Vpr, Nef and envelope glycoprotein gp120 on the NF-kB pathway, and in turn those that NF-kB exerts on HIV replication and apoptosis are well documented and were reviewed extensively (reviewed in Barkett and Gilmore, 1999;Hiscott et al, 2001;Santoro et al, 2003). The herpes simplex virus 1 envelope glycoprotein D and hepatitis C virus core protein induce NF-kB and confer resistance to apoptotic stimuli-like TNFa (Tai et al, 2000;Goodkin et al, 2003;Medici et al, 2003). Encephalomyocarditis virus (EMCV) also abrogates apoptosis via NF-kB as a means to enhance its pathogenic effects.…”

Section: Implication Of Nf-kb In the Cell Response To Viral Infectionmentioning

confidence: 99%

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

et al. 2003

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Section: Implication Of Nf-kb In the Cell Response To Viral Infectionmentioning

confidence: 99%

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

et al. 2003

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“…Several lines of evidence suggest that the NF-B family of proteins is involved in tumor growth and metastasis, where a high level of NF-B activity has been observed (33,36). Similarly, the chronic hepatitis C liver tissues displayed elevated levels of NF-B compared with the normal liver (39). NF-B induces expression of antiapoptotic genes, such as IAP protein, or genes that contribute to proliferation such as myc and Bcl-2 (36).…”

Section: Discussionmentioning

confidence: 99%

Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-κB

Gong

Waris

Tanveer

et al. 2001

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

552

476

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The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus RNA genome is shown here to induce the activation of NF-B and STAT-3 transcription factors from its cytoplasmic residence via oxidative stress. NS5A causes the disturbance of intracellular calcium. Ca 2؉ signaling triggers the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-B and STAT-3 into the nucleus. Evidence is presented for the constitutive activation of STAT-3 by NS5A. In the presence of antioxidants [pyrrolidine dithiocarbamate (PDTC), N-acetyl L-cysteine (NAC)] or Ca 2؉ chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-B and STAT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis associated with the viral infection.H epatitis C virus (HCV) causes acute͞chronic hepatitis with a significant risk of end-stage cirrhosis and hepatocellular carcinoma (1). The single-stranded RNA genome of the human HCV is a 9.6-kb-long positive-sense molecule, which encodes a polyprotein of about 3,000 aa (2, 3). The polyprotein is posttranslationally cleaved by both viral͞cellular proteases to produce about 10 polypeptides that include structural (core and E1 and E2) and nonstructural (NS2, NS3-NS5A͞B) proteins (2, 3). The single long ORF is preceded by 332 or 342 nt of the 5Ј untranslated region, which harbors an internal ribosome entry site capable of initiating translation at an internal site (4-6). The 3Ј end of the RNA genome contains a unique sequence of the untranslated region that is necessary for initiating RNA replication. Although the infectious cDNA clones that have been generated could infect chimpanzees, they failed to replicate in vitro in cultured cell lines (7). Lohmann et al. (8) described the generation of efficient replicating HCV RNA subgenomic replicons coexpressing a neomycin-resistance marker. A high level of replication of subgenomic replicons was characterized, resulting from adaptive mutations, which were scattered throughout the HCV genes of the replicon (9, 10).The HCV NS5A has generated a significant level of interest as several cellular targets have been identified. NS5A is a serine phosphoprotein, which exists as a polypeptide of p56 or p58 with varying degrees of phosphorylation (11,12). The identity of cellular kinase(s) responsible for NSS5A phosphorylation has not been firmly established. NS4A, an integral membrane protein, has been shown to modulate NS5A phosphorylation at least for some HCV subtypes (13). NS5A is localized to the cytoplasm in the perinuclear reticular network characteristic of the endoplasmic reticulum (ER) membrane (3,14). NS5A came into prominence because of its suggested role in IFN resistance. It was shown that NS5A directly interacted with double-stranded RNA-dependent kinase (PKR) and inactivated its function, thus modulating the IFN-stimulated antiviral response (15). Neither the sites of hyperphosphorylation nor the region designated ISDR (IFN-sen...

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“…Furthermore, the oncogenic HBV protein HBx and the HCV core and NS5B proteins were reported to induce NF-B. [29][30][31] The natural conclusion from these observations was that NF-B operates as a tumor promoter in virus-infected or transformed hepatocytes.…”

Section: Nf-b As a Tumor Suppressor In Hepatocytesmentioning

confidence: 99%

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

2007

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Nuclear factor-B (NF-B) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-B in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-B activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma-a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-B signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590-597.)

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Activation of nuclear factor ?B in hepatitis C virus infection: Implications for pathogenesis and hepatocarcinogenesis

Cited by 180 publications

References 73 publications

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-κB

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

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