2004 Fiscal Year Final Research Report Summary
Molecular mechanism for the development of gastric lesions by Helicobacter pylori infection
| 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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| Keywords | Helicobacterpylori / CagA / tyrosine phosphorylation / molecular polymorphism / SHP-2 / K-ras / ESXR1 / cancer gene therapy |
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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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[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
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
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Association between diversity in the Sic 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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[Journal Article] The diversity of vacA and cagA genes of Helicobacter pylori in East Asia.2004
Author(s)
Zhou, W., Yamazaki, S., Yamakawa, A., Ohtani, M., Ito, Y., Keida, Y., Higashi, H., Hatakeyama, M., Si, J, Azuma, T.
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Journal Title
FEMS Immunol.Med.Microbiol. 40
Pages: 81-87
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Helicobacter pylori CagA provokes Ras independent morphogenetic response through targeting SHP-2.2004
Author(s)
Higashi, H., Nakaya, A., Tsutsumi, R., Yokoyama, K., Fujii, Y., Higuchi, M., Takahashi, A., Kurashima, Y., Ishikawa, S., 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
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[Journal Article] Distinct diversity of the cag pathogenicity island of Helicobacter pylori in Japan.2004
Author(s)
Azuma, T., Yamakawa, A., Yamazaki, S., Ohtani, M., Ito, I, Muramatsu, A., Suto, H., Yamazaki, Y., Keida, Y., Higashi, H, Hatakeyama, M.
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Journal Title
J.Clin.Microbiol. 42
Pages: 2508-2517
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The paired-like horneodomain 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
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[Journal Article] Regulation of human T cell leukemia virus type-1 (HTLV-1) budding by ubiquitin ligase Nedd4.2004
Author(s)
Sakurai, A., Yasuda, J., Takano, H., Tanaka, Y., Hatakeyama, M, Shida, H.
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Journal Title
Microbes Infect. 6
Pages: 150-156
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa.2003
Author(s)
Yamazaki, S., Yamakawa, A., Ito, Y., Ohtani, M., Higashi, H., Hatakeyama, M, Azuma, T.
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Journal Title
J.Infect.Dis. 187
Pages: 334-337
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] NF-_B-dependent induction of cyclin D1 by pRB family proteins and tumor-derived pRB mutants.2003
Author(s)
Takebayashi, T., Higashi, H., Sudo, H., Ozawa, H., Suzuki, E., Shirado, O., Katoh, H, Hatakeyama, M.
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Journal Title
J.Biol.Chem. 278
Pages: 14897-14905
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma.2003
Author(s)
Umehara, S., Higashi, H., Ohnishi, N., Asaka, M, Hatakeyama, M.
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Journal Title
Oncogene 22
Pages: 8337-8342
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.2002
Author(s)
Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T., Asaka, M, Hatakeyama, M.
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Journal Title
Science 295
Pages: 683-686
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites.2002
Author(s)
Higashi, H., Tsutsumi, R., Fujita, A., Yamazaki, S., Asaka, M., Azuma, T, Hatakeyama, M.
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Journal Title
Proc.Natl.Acad.Sci.USA 99
Pages: 14428-14433
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Role of pRB-family/E2F complex in the inhibition of IL-3-dependent lymphoid cell proliferation.2002
Author(s)
Yamada, M., Kondo, T., Ashizawa, S., Takebayashi, T., Higashi, H, 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] SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein.2001
Author(s)
Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T., Asaka, M, 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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