| Project/Area Number |
09557192
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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 | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | HIROSHIMA UNIVERSITY (1998)
The University of Tokyo (1997) |
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Principal Investigator |
HIZEKI Osamu Hiroshima University Faculty of Medicine Professor, 医学部, 教授 (80142751)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMURA Naoki Hiroshima University Faculty of Medicine Research Associate, 医学部, 助手 (30144827)
KUROKAWA Tomonori Hiroshima University Faculty of Medicine Associate Professor, 医学部, 助教授 (00124793)
仁科 博史 東京大学, 大学院・薬学系研究科, 助手 (60212122)
星野 真一 東京大学, 大学院・薬学系研究科, 助手 (40219168)
柴崎 正勝 東京大学, 大学院・薬学系研究科, 教授 (30112767)
堅田 利明 東京大学, 大学院・薬学系研究科, 教授 (10088859)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | PI 3-KINASE / WORTMANNIN / G-PROTEINS / TYROSINE KINASE / SYNERGISM / PROTEIN KINASE B / METASTASIS / 阻害薬 / イノシトールリン脂質3-キナーゼ / ワ-トマニン |
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| Research Abstract |
Wortmannin, a potent inhibitor of phosphoinositide 3-kinase, and its derivatives were utilized to investigate the functions of the enzyme.
1. A novel catalytic subunit of phosphoinoside 3-kinase was isolated by use of a radiolabeled derivative of wortmannin. This subunit had a primary structure very similar to the beta-subtype of phosphoinositide 3-kinase. The novel subtype and the beta-subtype were found to be synergistically activated by a tyrosine-phosphorlated peptide and beta/gamma subunits of GYP-binding proteins. The alpha and gamma subtypes did not show the similar property.
2. The above synergism in vitro was operating in intact cell systems including rat adipocytes. The synergism was also observed as the cellular activity of protein kinase B, a downstream target of phosphoinositide 3-kinase. Thus a functional difference between the subtypes of the lipid kinase was newly suggested.
3. Wortmannin was found to inhibit the in vitro adhesion and motility of highly metastatic hepatoma cells. The effect was reproduced by introducing a dominant-negative mutant of phosphoinositide 3-kinase to the cells. Thus the enzyme was suggested to regulate the metastatic activity of hepatoma cells.
4. Derivatives of wortmannin lacking an ability to bind covalently to phosphoinositide 3-kinase were found. The compounds are expected to be utilized as ligands for affinity chromatography.
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