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Originally published In Press as doi:10.1074/jbc.M308898200 on November 20, 2003
J. Biol. Chem., Vol. 279, Issue 8, 7024-7028, February 20, 2004
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, and
Toshiya Hirayama¶¶
From the
Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan, the Department of Medical Technology, School of Health Sciences, Okayama University, Okayama 7008558, Japan, ¶PRESTO, Japan Science and Technology Agency, Saitama 3320012, Japan, the ||Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, Nagasaki 8528521, Japan, the **Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki 4448585, Japan, the Department of Endoscopy, Kobe University School of Medicine, Kobe 6578501, Japan, and the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892
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.
Received for publication, August 12, 2003
, and in revised form, November 10, 2003.
* This work was supported by grants-in-aid for scientific research from the Ministry of Education, Sports, Science, and Technology of Japan and from the Uehara Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶¶ To whom correspondence should be addressed. Tel.: 81-95-849-7831; Fax: 81-95-849-7805; E-mail: hirayama{at}net.nagasaki-u.ac.jp.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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