| Project/Area Number |
16590938
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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 |
Hematology
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| Research Institution | Osaka University |
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Principal Investigator |
MIZUKI Masao Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 講師 (80283761)
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| Co-Investigator(Kenkyū-buntansha) |
KANAKURA Yuzuru Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (20177489)
MATSUMURA Itaru Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00294083)
SHIBAYAMA Hirohiko Osaka University, Graduate School of Medicine, Instructor, 医学系研究科, 助手 (60346202)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | c-Kit / FLT3 / leukemia / AML / signal transduction / oncogenesis / chaperone / activation loop / 分子標的療法 / チロシンキナーゼ / 急性骨髄性白血病 / 活性化変異 / c-Kit / tyrosine kinase / oncogene / leukemia / mutation / chaperone |
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| Research Abstract |
Constitutive active mutants of tyrosine kinases are the key genetic abnormality of cancer. In hematological malignancies, constitutive active mutants of receptor tyrosine kinases such as c-Kit and FLT3 have been identified as the critical mutations in acute myeloid leukemia. We have studied the mechanism of leukemogenesis by these constitutive active receptor tyrosine kinases. Since tyrosine residues in the cytoplasmic domain of receptor tyrosine kinases regulate the activation and the downstream signal transduction, we investigated the critical tyrosine residues which regulate the constitutive activation of mutant receptor tyrosine kinases. By analyzing the Tyr-Phe mutations of each 22 tyrosine residue of FLT3 Asp838Val, constitutive active mutant of FLT3, we identified that Tyr845,Tyr892, and Tyr922 are the critical tyrosine residues which regulated the activation of FLT3Asp835Val mutant. The Tyr 845Phe,Tyr892Phe and Tyr922Phe mutations abolished the kinase activation itself of FLT3 Asp835Val, leading to the inhibition of full signal transduction, proliferation and survival. The suppressed kinase activity of these Tyr-Phe mutants were partially rescued by shifting the temperature to 33℃, and co-expression of chaperone proteins, Cdc38 and Hsp90. These results suggested that Tyr845,Tyr892 and Tyr922 may be the critical tyrosine residues which maintain the active conformation of FLT3 Asp835Val mutant. We have already identified that the tyrosine residue, Tyr7l9,critically regulated the activation of c-Kit Asp8l4Val mutant, which is the corresponding mutant to FLT3 Asp835Val. Taken together, the constitutive active mutants of receptor tyrosine kinase have the specific tyrosine residues which regulate the oncogenic activation, which may serve as the new specific targets of tyrosine kinase inhibitors.
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