title: Hepatitis B virus X stimulates redox signaling through activation of ataxia telangiectasia mutated kinase.
abstract: Hepatitis B virus X (HBX) protein plays a crucial role in carcinogenesis, but its mechanism is unclear. The involvement of ataxia telangiectasia mutated (ATM) kinase in the enhanced redox system was investigated by examining the phosphorylation level of ATM in HBX gene-transfected cells and in transgenic mice following redox system manipulation by treatment with hydrogen peroxide (H2O2) or antioxidant. Western blotting and immunostaining showed that phospho-ATM was significantly increased by HBX both in vitro (3.2-fold; p<0.05) and in vivo (4-fold; p<0.05), and this effect was abrogated by antioxidant treatment. The level of PKC-δ in HBX-expressing cells was increased 3.5-fold compared to controls. Nuclear localized NF-E2-related factor 2 (Nrf2) was increased in HBX-expressing cells exposed to H2O2, but remained at lower levels after the treatment with rottlerin, KU55933, or caffeine. The levels of anti-oxidant molecules were increased in HBX expressing cells and in transgenic mice, indicating that HBX stimulates the Nrf2-mediated redox system. The levels of intracellular reactive oxygen species (ROS) were significantly increased in HBX-expressing cells treated with hydrogen peroxide in the presence of ATM inhibitor KU55933 or caffeine. Treatment of HBX-expressing cells with KU55933 or caffeine before the exposure to H2O2 increased the ratio of cell apoptosis to 33±4% (p<0.05) and 22±4% (p<0.05), respectively. Collectively, HBX stimulates the ATM-mediated PKC-δ/Nrf2 pathway, and maintains the enhanced activity of the redox system. Therefore, manipulating ATM kinase activity might be a useful strategy for treating HBX-induced carcinogenesis.
authors: Department of Medical Technology, Niigata University Graduate School of Health Sciences 2-746 Asahimachi-dori, Chuo-Ku, Niigata 951-8518, Japan.
authors: Yasunobu
authors: Y
authors: Matsuda
authors: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Ayumi
authors: A
authors: Sanpei
authors: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Toshifumi
authors: T
authors: Wakai
authors: Division of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Masayuki
authors: M
authors: Kubota
authors: Division of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Mami
authors: M
authors: Osawa
authors: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Yuki
authors: Y
authors: Hirose
authors: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Jun
authors: J
authors: Sakata
authors: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Takashi
authors: T
authors: Kobayashi
authors: Department of Medical Technology, Niigata University Graduate School of Health Sciences 2-746 Asahimachi-dori, Chuo-Ku, Niigata 951-8518, Japan.
authors: Shun
authors: S
authors: Fujimaki
authors: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Masaaki
authors: M
authors: Takamura
authors: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Satoshi
authors: S
authors: Yamagiwa
authors: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Masahiko
authors: M
authors: Yano
authors: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Shogo
authors: S
authors: Ohkoshi
authors: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors: Yutaka
authors: Y
authors: Aoyagi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000975:Antioxidants; D050984:NF-E2 Transcription Factor, p45 Subunit; C494692:NFE2 protein, human; C494693:Nfe2 protein, mouse; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C497259:Prkcd protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta
keywords: Hepatitis B virus X; ataxia telangiectasia mutated; reactive oxygen species