| Project/Area Number |
14370171
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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) |
ASAKA Masahiro Hokkaido Univ., Grad.School of Med., Prof, 大学院・医学研究科, 教授 (10113507)
AZUMA Takeshi Fukui Univ., Internal Med., Asso., Prof, 内科学第二講座, 助教授 (60221040)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2002: ¥6,400,000 (Direct Cost: ¥6,400,000)
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| Keywords | Helicobacterpylori / CagA / tyrosine phosphorylation / molecular polymorphism / SHP-2 / K-ras / ESXR1 / cancer gene therapy / トランスジェニックマウス / 胃癌 / 転写制御 / 分子多型性 / オーダーメイド治療 |
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| Research Abstract |
Helicobacter pylori (H. pylori) strains carrying the cagA gene are more virulent than cagA-negative strains and are associated with the development of gastric adenocarcinoma. The cagA gene product, CagA, is translocated into gastric epithelial cells and localizes to the inner surface of the plasma membrane, where it undergoes tyrosine phosphorylation at the EPIYA motifs. Tyrosine-phosphorylated CagA specifically binds and activates SHP-2 tyrosine phosphatase and the C-terminal Src kinase (Csk), thereby inducing an elongated cell shape termed the hummingbird phenotype. CagA species of H.pylori isolated in East Asian countries exhibit stronger SHP-2 binding activity and greater pathobiological activity than those isolated in Western countries. Thus, populations infected with East Asian cagA-positive H.pylori may be at greater risk for gastric cancer than those infected with Western cagA-positive or cagA-negative strains.
Gain-of-function mutation of the K-ras gene is one of the most commo
… More
n genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is not only essential for the tumorigenesis but also necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein. The full-length ESXR1 protein is proteolytically processed into an N-terminal fragment containing the homeodomain and a C-terminal fragment. The full-length ESXR1 and the C-terminal fragment are localized to the cytoplasm, whereas the N-terminal homeodomain-containing ESXR1 fragment is exclusively localized within the nucleus. The N-terminal ESXR1 fragment represses K-ras mRNA transcription by binding to the TAATGTTATTA sequence present within the first intron of the human K-ras gene. Expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of the K-ras gene has an important implication for the development of cancer therapy that targets oncogenic K-ras. Less
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