| Project/Area Number |
12213140
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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 | Japanese Foundation for Cancer Research |
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Principal Investigator |
NAKAMURA Takuro The Cancer Institute, Department of Caranogenesis, Chief, 癌研究所発がん研究部, 部長 (00180373)
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| Co-Investigator(Kenkyū-buntansha) |
KOMINAMI Ryo Niigata University, Department of Biochemistry, Professor, 大学院・医歯学総合研究科, 教授 (40133615)
IWASAKI Masayuki The Cancer Institute, Department of Carcanogenesis., AttendingAssodate, 癌研究所発がん研究部, 特別研究員(PD)
YAMAGUCHI Shuichi The Cancer Institute, Department of Carcanogenesis., Attending Associate, 癌研究所発がん研究部, 研究員
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥84,900,000 (Direct Cost: ¥84,900,000)
Fiscal Year 2004: ¥17,100,000 (Direct Cost: ¥17,100,000)
Fiscal Year 2003: ¥17,500,000 (Direct Cost: ¥17,500,000)
Fiscal Year 2002: ¥18,000,000 (Direct Cost: ¥18,000,000)
Fiscal Year 2001: ¥17,300,000 (Direct Cost: ¥17,300,000)
Fiscal Year 2000: ¥15,000,000 (Direct Cost: ¥15,000,000)
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| Keywords | Evi9 / Bcllla / Ritl / Bclllb / BXH2 / myeloid leukemia / thymic lymphoma / NUP98-HOXA9 / Meisl / retroviral insertional mutaenesis / アポトーシス / BHX2 / BHX2マウス / BXH-2マウス / 転写調節 / 分化 |
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| Research Abstract |
We engaged in the current study using retrovirus-and radiation-induced mouse hematopoietic tumor models. The major genes of subject in each model were Evi9/Bcl11a and Rit1/Bcl11b, both of which belong to the Bcl11 gene family and play an important role in the development of B-cell and T-cell, respectively. Evi9/Bcl11a is a human B-cell oncogene and a murine myeloid oncogene. We have revealed that Bcl11a is essential for B-cell development using a Bcl11a knockout model and the Bcl11a activity for B-cell development might be related to its transcriptional regulatory activity on the immunoglobulin heavy chain enhancer with E2A. It was also shown that Bcl11a plays an important role in T-cell development. To the contrary, Rit1/Bcl11b has been identified as a tumor suppressor in mouse thymic lymphoma. Analysis of the Bcl11b knockout mouse revealed that Bcl11b is essential for T-cell development and loss of Bcl11b results in apoptosis of T-cells. There was significantly higher incidence of th
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ymic lymphoma in Bcl11b -/+ mice than in wild type littermates by □-irradiation. Approximately 50% of lymphoma showed loss of the wild type allele of Bcl11b. Moreover, Bcl11b -/+ and p53 -/+ double heterozygous mice frequently developed thymic lymphoma by 300 day of age without irradiation. Decrease of the Bcl11 protein induced apoptosis by downregulating the anti-apoptotic protein BclxL, cell cycle arrest at the S phase and inhibition of Chk1 phosphorylation. These results suggest that Bcl11b may interact with Chk1 and acts in genome stabilization funcion. Analyzing transgenic mice, it was shown that NUP98-HOXA9 induces G-CSF hypersensitivity of myeloid progenitors. Meis1 and novel 5 genes were identified as cooperative genes for NUP98-HOXA9 in leukemogenesis by using retroviral insertional mutagenesis. Among these genes Fcgr2b was found involved in human hematological malignancies, indicating that the model is important to understand molecular mechanisms of human leukemogenesis. Furthermore, MAPK signaling molecules and Mel1 were identified as candidate cooperative genes for NUP98-HOXA9 and HOX co-factors. Less
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