| Project/Area Number |
14032201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Osaka University |
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Principal Investigator |
OKADA Masato Osaka University, Research Institute for Microbial Diseases, Professor, 微生物病研究所, 教授 (10177058)
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| Co-Investigator(Kenkyū-buntansha) |
NADA Shigeyuki Osaka University, Research Institute for Microbial Diseases, Associate Professor, 微生物病研究所, 助教授 (50291448)
HIROSE Takashi Osaka University, Research Institute for Microbial Diseases, Assistant Professor, 微生物病研究所, 助手 (30343247)
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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 |
¥94,100,000 (Direct Cost: ¥94,100,000)
Fiscal Year 2004: ¥33,100,000 (Direct Cost: ¥33,100,000)
Fiscal Year 2003: ¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 2002: ¥26,000,000 (Direct Cost: ¥26,000,000)
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| Keywords | oncogene / cancer / tyrosine kinase / signal transduction / epithelia / Src / Csk / Rafts / 浸潤転移 / 上皮組織 / 細胞接着 / 線虫 / 遺伝子 / 癌 / 酵素 / 発生・分化 / SFK / Cbp |
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| Research Abstract |
To develop new strategies to suppress carcinogenesis and to control cancer progression, it is critical to understand the fundamental roles and regulatory features of proto-oncogene and anti-oncogene products at the molecular level. In this study, we extensively analyzed the normal functions and regulation of the src family of proto-oncogene products (SFK) in order to understand the role played by SFK in cancer progression, and particularly in the acquisition of metastatic activity.
1. Studies of epithelial cancer cells and mutant mice that lack Csk, a negative regulator of SFK, revealed that SFK plays critical roles in cell migration and in the regulation of the epithelial-like cell to mesencymal-like cell transition (EMT). It was also found that SFK is involved in the cell-cell adhesion required for the maintenance of cell polarity and for the regulation of cell proliferation through the control of cytoskeletal organization. Cortactin, an actin binding protein, and its associated molec
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ules were identified as potential targets of SFK in the epithelial-like cell to mesencymal-like cell transition. Furthermore, Csk acted as the critical regulator of these phenomena, suggesting that Csk could be used as a potential therapeutic target to control cancer progression and/or metastasis. 2. In the lipid raft fraction that provides a platform for SFK signaling, we identified a novel membrane phosphoprotein Cbp (Csk binding protein) as an initial target of SFK, and showed that it serves as a membrane scaffold protein for Csk. 3. To analyze the fundamental roles of SFK in animals, we identified SFK and Csk orthologues in C. elegans. Analysis of mutant worms revealed that SRC-1, an orthologue of Src, plays an essential role in controlling the migration of specific cell types during organogenesis. The Rac signaling pathway was identified as a downstream target of SRC-1. 4. Based on the structural information provided by the crystal structure of Csk, we proposed a molecular basis for SFK regulation by Csk. Less
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