| Project/Area Number |
07457229
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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 |
Hematology
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| Research Institution | University of Tokyo |
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Principal Investigator |
HIRAI Hisamaru University of Tokyo, Hospital, Internal Medicine, Associate Professor, 医学部・附属病院, 助教授 (90181130)
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| Co-Investigator(Kenkyū-buntansha) |
KUROKAWA Mineo University of Tokyo, Hospital, Internal Medicine, Research Staff, 医学部・附属病院, 医員
OGAWA Seishi University of Tokyo, Hospital, Internal Medicine, Research Staff, 医学部・附属病院, 助手
TANAKA Tomoyuki University of Tokyo, Hospital, Internal Medicine, Assistant Professor, 医学部・附属病院, 助手 (50227154)
MITANI Kinuko University of Tokyo, Hospital, Internal Medicine, Assistant Professor, 医学部・附属病院, 助手 (50251244)
花園 豊 東京大学, 医学部(病), 助手 (70251246)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1996: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1995: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | AML1 gene / chromosomal translocation / transcription factor / extracellular signal-regulated kinase / myelogenous leukemias / phosphorylation / 染色体転座 / MAPキナーゼ / リン酸化 / 慢性骨髄性白血病 / AML1 / Evi-1融合蛋白質 / 転写活性 / 細胞増殖 / 細胞分化 |
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| Research Abstract |
The AML1 gene on chromosome 21 is disrupted in the (8 ; 21) (q22 ; q22) and (3 ; 21) (q26 ; q22) translocations associated with myelogenous leukemias and encodes a transcription factor. From AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by an alternative splicing. Overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dc13 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects by AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that AML1a, which solely has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and that AML1a exhibits the higher affinity for DNA-binding than AML1b. These antagonistic actions could be important for leukemogenesis and/or myeloid cell differentiation.
We also investigate the regulatory mechanisms of AML1 functions through signal transduction pathways. AML1 is phosphorylated in vivo on two serine residues within the proline-, serine- and threonine-rich region, with dependence on the activation of extracellular signal-regulated kinase (ERK). These in vivo phosphorylation sites of AML1 were directly phosphorylated in vitro by ERK.Although alterations in the DNA-binding affinity were not observed between wild AML1 and non-phosphorylated mutants, we have shown that ERK-dependent phosphorylation potentiates the transactivation ability of AML1. Furthermore the phosphorylation site-mutations reduced the transforming capacity of AML1 in fibroblast cells. These data suggest that AML1 functions are regulated by ERK which is activated by cytokine or growth facotr-stimuli. This study would give important clues to clarify unidentified facets of regulatory mechanisms of AML1 function.
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