Disturbance of intracellular SHP-2 activity and cell growth regulation by Helicobacter pylori CagA
| Project/Area Number |
15590264
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Helicobacter pylori / CagA / SHP-2 / FAK / Ras / DNA chip / protein phosphorylation / 癌 / シグナル伝達 / 感染症 |
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| Research Abstract |
1.We established AGS human gastric epithelial cells that conditionally express CagA by employing Tet-On system. The cells expressing CagA exhibited the growth factor-like morphological change as in the case of cagA-positive H.pylori infection. Using the cells, we investigated the CagA effect on Ras/MAPK pathway. As results, we revealed that the morphological change induced by CagA was dependent on MAPK activity but not on Ras activity. On the other hand, we observed that tyrosine phosphorylation levels of tyrosine kinase FAK decreased in CagA-expressing cells. SHP-2 directly dephosphorylates FAK phosphorylation sites which associate with FAK activation, and thereby inactivates FAK. From these results, we clarified that CagA disrupt intracellular signaling by in activation of FAK through SHP-2 activation as well as activation of Ras-independent MAPK cascade.
2.We analyzed changes in gene expression caused by ectopic expression of the cagA gene in gastric epithelial cells using a DNA microarray, and accordingly found multiple cagA-responsive genes. Analyzing putative promoter sequences of the cagA-responsive genes, binding sites for particular transcription factors were significantly over-represented in the promoter regions of CagA-activated genes. Furthermore, we found that CagA is capable of activating gene transcription which is dependent on a specific transcriptional factor in the cells. It is suggested that CagA biological activity causes dysregulation of intracellular gene-expression profile.
3.We constructed cagA transgenic mouse to investigate CagA biological activity and the mechanism of CagA mediated-development of gastric cancer in vivo. We have established several transgenic lines which show expression of cagA gene.
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Report
(3 results)
Research Products
(44 results)
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[Journal Article] Paired-like homeodornain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation.2004
Author(s)
Ozawa H., Ashizawa S., Naito M., Yanagihara M., Ohnishi N., Maeda T., Matsuda Y., Jo Y., Higashi H., Kakita A., Hatakeyama M.
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Journal Title
Oncogene 23
Pages: 6590-6602
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Distinct diversity of the cag pathogenicity island among Helicobacter pylori strains in Japan.2004
Author(s)
Azuma T., Yamakawa A., Yamazaki S., Ohtani M., Ito Y., Muramatsu A., Suto H., Yamazaki Y., Keida Y., Higashi H., Hatakeyama M.
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Journal Title
J.Crin.Microbiol. 42
Pages: 2508-2517
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP-2 recruitment and activation.2004
Author(s)
Higashi H., Nakaya A., Tsutsumi R., Yokoyama K., Fujii Y., Ishikawa S., Higuchi M., Takahashi A., Kurashima Y., Teishikata Y., Tanaka S., Azuma T., Hatakeyama M.
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Journal Title
J.Biol.Chem. 279
Pages: 17205-17216
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Association between diversity in the Src homology 2 domain-containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer.2004
Author(s)
Azuma T., Yamazaki S., Yamakawa A., Ohtani M., Muramatsu A., Suto H., Ito Y., Dojo M., Yamazaki Y., Kuriyama M., Keida Y., Higashi H., Hatakeyama M.
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Journal Title
J.Infect.Dis. 189
Pages: 820-827
Description
「研究成果報告書概要(欧文)」より
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[Book] 細胞工学232004
Author(s)
東 秀明
Total Pages
4
Description
「研究成果報告書概要(和文)」より
Related Report
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[Book] 生化学752003
Author(s)
東 秀明
Total Pages
3
Description
「研究成果報告書概要(和文)」より
Related Report
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