Helicobacter pylori VacA Activates the p38/Activating Transcription Factor 2-mediated Signal Pathway in AZ-521 Cells

Masaaki Nakayama, Miyuki Kimura, Akihiro Wada, Kinnosuke Yahiro, Ken Ichi Ogushi, Takuro Niidome, Akihiro Fujikawa, Daisuke Shirasaka, Nobuo Aoyama, Hisao Kurazono, Masaharu Noda, Joel Moss, Toshiya Hirayama

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77 Citations (Scopus)

Abstract

Persistent Helicobacter pylori colonization in the stomach induces gastritis and peptic ulcer and interferes with ulcer healing. Most strains of H. pylori produce a cytotoxin, VacA, that induces cytoplasmic vacuolation in epithelial cells with structural and functional changes, leading to gastric injury. VacA is known to cause cell death by mitochondrial damage. We hypothesized that VacA might disrupt other signaling pathways; to that end, we examined the effects of VacA on MAPKs to elucidate their role in the abnormalities seen in VacA-treated cells. VacA stimulated phosphorylation of p38 and Erk1/2, but not JNK, in AZ-521 cells. Both phosphorylation and kinase activation of p38 were maximal 10-30 min after addition of VacA and declined thereafter. Treatment with anti-VacA antibody or the p38 inhibitor SB203580 blocked p38 phosphorylation caused by VacA and inhibited VacA-induced phosphorylation of activating transcription factor 2 (ATF-2), which is implicated in transcriptional control of stress-responsive genes. These data indicate that VacA stimulates a p38/ATF-2-mediated signal pathway. However, 10 μm SB203580, which is sufficient to decrease p38 phosphorylation, did not inhibit VacA-induced cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria. These results suggest that VacA-induced activation of p38/ATF-2-mediated signal pathway is independent of cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria caused by VacA. The cytotoxin may thus act independently on several cellular targets, leading to disruption of signaling, regulatory, and metabolic pathways.

Original languageEnglish
Pages (from-to)7024-7028
Number of pages5
JournalJournal of Biological Chemistry
Volume279
Issue number8
DOIs
Publication statusPublished - Feb 20 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nakayama, M., Kimura, M., Wada, A., Yahiro, K., Ogushi, K. I., Niidome, T., Fujikawa, A., Shirasaka, D., Aoyama, N., Kurazono, H., Noda, M., Moss, J., & Hirayama, T. (2004). Helicobacter pylori VacA Activates the p38/Activating Transcription Factor 2-mediated Signal Pathway in AZ-521 Cells. Journal of Biological Chemistry, 279(8), 7024-7028. https://doi.org/10.1074/jbc.M308898200