| Project/Area Number |
13214034
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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 | Universly of Tsukuba |
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Principal Investigator |
NAGATA Kyosuke University, Graduate School of Medicine, Professor, 大学院人間総合科学研究科, 教授 (40180492)
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| Co-Investigator(Kenkyū-buntansha) |
KIKUCHI Akihiko Nagoya University, Graduate School of Medicne, Professor, 大学院医学研究科, 教授 (40283428)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥38,000,000 (Direct Cost: ¥38,000,000)
Fiscal Year 2004: ¥9,300,000 (Direct Cost: ¥9,300,000)
Fiscal Year 2003: ¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2001: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | chromatin / leukemia / translocation / histone chaperone / nuclear pore / si RNA / hCRM1 / trxG / シャペロン / 核-細胞質輸送 / ウイルス / 細胞周期 / 核孔 / クロマチンリモデリング / 分子シャペロン / ドミナントネガティブ変異体 / がん / 形質転換能 / 核外輸送 / ヌクレオポリン |
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| Research Abstract |
The ultimate goal of this study is to clarify the molecular and cellular mechanism of oncogenesis by chromatin remodeling factor-nucleoporin fusion genes such as TAF-I (Template Activating Factor-I) β/SET-CAN and DEK-CAN associated with myeloid leukemia. TAF-Iβ/SET is a histone chaperone and DEK is identified as a factor involved in regulation of the chromatin structure, while CAN, alternatively designated Nup214, is one of components of nuclear pore complexes.
Introduction of TAF-Iβ/SET-CAN into normal cells, for instance, NIH3T3 cells resulted in cell transformation and tumor formation in nude mice. TAF-Iβ-CAN was found to be present in the nucleus as distinct dots. hCRM1, an exportin that binds to CAN bound to TAF-Iβ-CAN, so that NES proteins, molecular targets of hCRM1, were found accumulated in the nucleus. Knock-down of expression of TAF-Iβ-CAN in TAF-Iβ-CAN-transformed cells with specific si RNA cancelled some of the cell transformation properties, suggesting that TAF-Iβ/SET-CAN is involved in cell transformation through at least two independent mechanisms. Studies on parts of the fusion gene products revealed several novel findings: TAF-Iβ/SET bound to MLL, a trxG family member, and was found to be involved in expression regulation of MLL target genes with MLL. TAF-II/NAP-1, a structural and functional homologue of TAF-Iβ/SET, regulated the mitotic progression through its nuclear export. It was found that TAF-III, a histone chaperone consists of nucleophosmin/B23 and RNA molecules. Experiments using dominant-negative mutants for the TAF-III activity showed that TAF-III is involved in regulation of rRNA synthesis through its chromatin regulation activity and thereby in cell growth rate control.
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