Molecular mechanisms underlying gastrointestinal lesions in transgenic mice expressing Helicobacter pylori cagA gene
| Project/Area Number |
17390211
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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 |
Gastroenterology
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
HATAKEYAMA Masanori HOKKAIDO Univ., Inst. for Genetic Med., Prof., 遺伝子病制御研究所, 教授 (40189551)
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| Co-Investigator(Kenkyū-buntansha) |
AZUMA Takeshi KOBE Univ., School of Mcd., Prof., 医学部, 教授 (60221040)
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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 |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2005: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | Helicobacter pylori / CagA / transgenic mouse / Western CagA / East Asian CagA / gastric mucosal lesion / tyrosine phosphory lation / EPIYA / 胃粘膜 / EPIYAモチーフ / 胃癌 |
|---|
| Research Abstract |
Infection with Helicobacter pylori is associated with chronic gastritis and peptic ulcers. In particular, H. pylori cagA-positive strains causes severe gastritis and have been suggested to play an important role in the development of gastric carcinoma. To investigate the direct role of H. pylori CagA in carcinogenesis, we generated transgenic mice that express ABDD-type East Asian CagA specifically in the gastric mucosa or throughout the body. Both of the CagA transgenic mice developed thickened gastric mucosa with epithelial cell hyperproliferation by 12 weeks of age. The findings indicate that CagA has a growth-promoting activity in a tissue-specific manner in vivo. To know if the CagA activity is dependent on CagA tyrosine phosphorylation, we generated transgenic mice that express a phosphorylation-resistant CagA, which was made by replacing the EPIYA tyrosine-phosphorylation motifs with the EPIYA sequences in the ABDD-type CagA. To understand the relationship between structural polymorphism and in vivo pathogenicity of CagA proteins, we also generated transgenic mice that express ABCCC-type Western CagA. Development of gastrointestinal lesions in these transgenic mice is currently under investigation.
Sequence analysis of the genes encoding East Asian CagA proteins from various clinical isolates revealed that there is also significant structural diversity among East Asian CagA species due to various genomic duplication and/or deletion, which was not recognized previously. Functional studies of these East Asian CagA proteins showed that the degree of individual CagA to bind SHP-2 depends on the number of EPIYA-D sites whereas that of CagA-Csk interaction is dependent on the number of EPIYA-A and-B sites.
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Report
(3 results)
Research Products
(73 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., Tcishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Peek, R.M., Jr., Azuma, T., Hatakeyama., M.
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「研究成果報告書概要(欧文)」より
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[Journal Article] Development of a novel method to detect Helicobacter pylori cagA genotype from paraffin-embedded materials : comparison between patients with duodenal ulcer and gastric cancer in voune Japanese.2006
Author(s)
Ueda, H., Ito, M, Eguchi, H., Tanaka, S.,.Yoshihara, M., haruma, K., Hatakeyama, M., Chayama, K.
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Journal Title
Digestion 73
Pages: 47-53
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Influence of EPIYA-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
Gas' terolory 130
Pages: 1181-1190
NAID
Description
「研究成果報告書概要(欧文)」より
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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., Ishikaw:4, S, Higashi, H., Tsutsui, H., Hatakeyama.M., Kitabatal:e, A.
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Journal Title
Biochem. Biophys. Rcs. 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] Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene.2005
Author(s)
Yanagihara, M., Ishikawa, S., Naito, M., Nakajima, J., Aburatani, H., Hatakeyama, M.
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Journal Title
Oncogene 24
Pages: 5878-5887
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, 1-1., 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] EPlYA 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] Activation of beta-catenin by carcinogenic Helicobacter pylori.2005
Author(s)
Franco, A.T., Israel, D.A., Washington, M.K., Krishna.U..Fox, J.G., Rogers, A.B., Neish, A.S., Collier-Hyams, L., Perez-Perez, G.1., Hatakevama, M..Whitehead, R., gaus, K., O'brien, D.P., Romero-Gallo, J., Peek, R.M.,.Jr.
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Journal Title
Proc. Natl. Acad. Sci. USA 102
Pages: 10646-10651
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., Hatakcevama.M., Azuma, T., Distinct diversity of vacA, cagA
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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 higly 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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