Study of H. pylori CagA-mediated gastric pathogenesis
| Project/Area Number |
17390087
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
HIGASHI Hideaki HOKKAIDO Univ., Inst. for Genetic Med., Asso. Prof., 遺伝子病制御研究所, 助教授 (20311227)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Keywords | gastric cancer / infection disease / Helicobacler pylori / tyrosine phosphorylation / transcriptional factor / ヘリコバクターピロリ |
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| Research Abstract |
1.Membrane association of CagA is important for the pathogenic action of CagA in gastric epithelial cells and requires the EPIYA motif but is independent of EPIYA tyrosine phosphorylation.
2.The activated SHP-2 with CagA directly dephosphorylates phospho-tyrosine residues of FAK, which are the activating phosphorylation sites. Accordingly, FAK activation is abolished in cells, and the inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA.
3.By screening of CagA-responsive genes using DNA microarray, we identified NFAT. CagA induced nuclear translocation and transcriptional activity of NFAT depending on calcineurin/PLC_γ pathway. Furthermore, H. pylori VacA toxin counteracted the ability of CagA to activate NFAT.
4.Using a series of EPIYA-repeat variants of CagA that represent reported variations in clinical isolates of H. pylori, we show that EPIYA-repeat polymorphism, 'which is due to differences of both number and order of EPIYA segment, influences the phosphorylation-dependent CagA biological activity.
5.We identified CagA multimerization motif that is composed of 16 amino acid residues and mediates an intermolecular interaction between CagA molecules. The CagA multimerization is necessary to express CagA biological activity 'that relates with cell morphogenetic activity and stimulation of cell motility.
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Report
(3 results)
Research Products
(32 results)
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[Journal Article] Helicobacter pylori CagA associates with E-cadherin and deregulates β -catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells.2007
Author(s)
Murata-Kamiya, N., Kurashima, Y., Teishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Peek, R.M., Jr., Azuma, T., Hatakeyama, M.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Influence of EPI YA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA.2006
Author(s)
Naito, M., Yamazaki, T., Tsutsumi, R., Higashi, H., Onoe, K., Yamazaki, S., Azuma, T., Hatakeyama, M.
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Journal Title
Gastroenterolory 130
Pages: 1181-1190
NAID
Description
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[Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells.2005
Author(s)
Nakano, N., Urasawa, K., Takagi, Y., Saito, T., Kaneta, S., shikawa, S., Higashi, H., Tsutsui, H., Hatakeyama, M., Kitabatake, A.
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Journal Title
Biochem. Biophys. Res. Commun. 338
Pages: 1661-1667
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.2005
Author(s)
Yokoyama, K., Higashi.H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, H., Azuma, T., Wada, A., Hirayama, T., Aburatani, H., Hatakeyama, M.
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Journal Title
Proc. Natl. Acad. Sci. USA 102
Pages: 9661-9666
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells.2005
Author(s)
Higashi, H., Yokoyama, K., Fujii, Y., Ren, S., Yuasa, H., Isaadat, I., Murata-Kamiya, N., Azuma, T., Hatakeyama, M.
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Journal Title
J. Biol. Chem. 280
Pages: 23130-23137
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Distinct diversity of vacA cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan.2005
Author(s)
Yamazaki, S., Yamakawa, A., Okuda, T., Ohtani, M., Suto H., Ito, Y., Yamazaki, Y., Keida, Y., Higashi, H.Hatakeyama, M., Azuma, T.
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Journal Title
J. Clin. Microbiol. 43
Pages: 3906-3916
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using highly sensitive real-time PCR as a new diagnostic tool. FEMS Immunol.2005
Author(s)
Yamazaki, S., Kato, S., Matsukura, N., Ohtani, M., Ito, Y., Suto, H., Yamazaki, Y., Yamakawa, A., Tokudome, S., Higashi, H., Hatakeyama, M., Azuma, T.
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Journal Title
FEMS Immunol. Med. Microbiol. 44
Pages: 261-268
Description
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