| Project/Area Number |
17390273
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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 | The University of Tokyo |
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Principal Investigator |
KUROKAWA Mineo The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (80312320)
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| Co-Investigator(Kenkyū-buntansha) |
HANGAISHI Akira The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 特任講師 (20344450)
IZUTSU Koji The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (30361471)
GOYAMA Susumu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 医員 (80431849)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2005: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | Evi-1 / leukemia / isoform / oligomerization / knockout mice / hematopoietic stem cell / 多量体 / 造腫瘍性 / TGF-β / CtBP / AML1-Evi-1 / AP-1 |
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| Research Abstract |
Evi-1 is a member of the SET/PR domain family of transcription factors whose inappropriate expression leads to leukemic transformation. Two distinct alternative forms, Evi-1a and Evi-1c, are generated from the Evi-1 gene. Although Evi-1a (PR-absent form) is widely recognized as an oncoprotein, a role for Evi-1c (PR-containing form) in leukemogenesis has not been elucidated. In this study, we showed that Evi-la forms homo-oligomers while Evi-1c exclusively exists as a monomer. Remarkably, Evi-1c has lost the ability to interact with CtBP, and to repress TGF-β signaling. These results indicate that oligomeraization contributes to the oncogenic potential of Evi-1.
Next, We created Evi-1 mutant mice to investigate the in vivo role of Evi-1 in hematopoiesis and leukemogenesis. Using these mice, we showed that Evi-1 regulates proliferative capacity of hematopoietic stem cells in a dose-dependent manner both during embryogenesis and in adults. In contrast, Evi-1 is dispensable for blood cell lineage commitment. We further demonstrated that disruption of Evi-1 in leukemic cells transformed by MLL/ENL or E2A/HLF leads to significant loss of their proliferative activity. These results suggest that Evi-1 is a critical regulator for the proliferation of normal and leukemic cells.
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