Reactive oxygen species modulates the intracellular level of HBx viral oncoprotein

Wang, Jin Hee; Yun, Chawon; Kim, Sujeong; Lee, Jae Ho; Yoon, Gyesoon; Lee, Mi Ock; Cho, Hyeseong

doi:10.1016/j.bbrc.2003.08.113

Cited by 26 publications

(25 citation statements)

References 42 publications

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“…Because HBx induces oxidative stress in liver cells, we hypothesized that HBx causes DNA damage through ROS generation. As previously shown by our group and others (Lim et al, 2010;Wang et al, 2003;Waris et al, 2001), transfection of pMyc-HBx into Chang cells increased cellular ROS levels in a time-dependent manner (Fig. 4a, left).…”

Section: Hbx Increases Cellular Ros Levels Which Correlate With Actisupporting

confidence: 83%

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

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Genetic instability is intimately associated with tumour development. In particular, liver cancers associated with hepatitis B virus (HBV) exhibit high genetic instability; however, our understanding of the underlying molecular mechanisms remains limited. In this study, we found that c-H2AX, a marker of DNA double-strand breaks (DSBs), and the levels of phospho-Chk2 (p-Chk2, the activated form) were significantly elevated in HBV-associated hepatocellular carcinomas and neighbouring regenerating nodules. Likewise, introduction of the pHBV or pMyc-HBx plasmids into cells induced accumulation of c-H2AX foci and increased the p-Chk2 level. In these cells, inhibitory phosphorylation of Cdc25C phosphatase (Ser 216 ) and CDK1(Tyr 15 ) was elevated; consequently, cell-cycle progression was delayed at G 2 /M phase, suggesting that activation of the ATM-Chk2 pathway by the HBV X protein (HBx) induces cell-cycle delay. Accordingly, inhibition of ataxia telangiectasia mutated (ATM) by caffeine or siRNA abolished the increase in the p-Chk2 level and restored the delayed CDK1 kinase activity in ChangX cells. We also found that cytoplasmic HBx, but not nuclear HBx, induced reactive oxygen species (ROS) production and led to the accumulation of c-H2AX foci and the increased p-Chk2 level. Together, these data indicate that HBx-induced ROS accumulation induces DNA damage that activates the ATM-Chk2 pathway. Our findings provide insight into the mechanisms of HBV pathogenesis.

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Section: Hbx Increases Cellular Ros Levels Which Correlate With Actisupporting

confidence: 83%

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

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“…Other studies suggest that HBx induces apoptosis by sensitizing cells and tissues to H 2 O 2 (19). Notably, ROS accumulation has been shown to upregulate HBx expression (39). In the present study, the concentration of H 2 O 2 we used did not show an apparent change in ROS levels in HBx-expressing cells or the control group, however, it induced a significant enhancement of ROS levels in the pHBV-expressing cells compared with the control group, demonstrating that HBx-induced ROS accumulation in normal liver cells was dependent on constitutively replicated HBV.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein sensitizes HL-7702 cells to oxidative stress-induced apoptosis through modulation of the mitochondrial permeability transition pore

Gao

Cai

et al. 2016

Oncology Reports

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Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and cancer. Among the pathogenic factors of HBV, HBV X protein (HBx) is attracting increased attention. Although it is documented that HBx is a multifunctional regulator that modulates cell inflammation and apoptosis, the exact mechanism remains controversial. In the present study, we explored the effect of HBx on oxidative stress-induced apoptosis in normal liver cell line, HL-7702. Our results showed that the existence of HBx affected mitochondrial biogenesis by modulating the opening of the mitochondrial permeability transition pore (MPTP). Notably, this phenomenon was associated with a pronounced translocation of Bax from the cytosol to the mitochondria during the period of exposure to oxidative stress with a release of cytochrome c and activation of cleaved caspase-3 and PARP. Moreover, MPTP blockage with cyclosporin A prevented the translocation of Bax, and inhibited oxidative stress-induced apoptotic killing in the HBx-expressing HL-7702 cells. Our findings suggest that HBx exhibits pro-apoptotic effects upon normal liver cells following exposure to oxidative stress by modulating the MPTP gateway.

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“…They found that certain cell lines which were originally derived from HBV-infected livers (Hep3B, PLC/PRF/5) demonstrated increased nuclear staining of ␤-catenin and TCF-4-dependent transcription when cotransfected with Wnt-1 and ␤-catenin. 97 The PLC/ PRF/5 cell line has previously been shown to express low levels of HBx, 98 while HepB3 cells do not express HBx. 99 In addition, co-transfecting Huh-7 cells (derived from an HBV-negative liver) with HBx and Wnt-1 caused a dosedependent increase in TCF-4-dependent transcriptional activity, and increased nuclear translocation of ␤-catenin.…”

Section: Wnt/␤-cateninmentioning

confidence: 99%

Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

2006

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Reactive oxygen species modulates the intracellular level of HBx viral oncoprotein

Cited by 26 publications

References 42 publications

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Hepatitis B virus X protein sensitizes HL-7702 cells to oxidative stress-induced apoptosis through modulation of the mitochondrial permeability transition pore

Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

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