| Project/Area Number |
09470038
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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 |
Pathological medical chemistry
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
TAKURO Nakmura The Cancer Institute, Department of Carcinogenesis, Head, 癌研究所・発がん研究部, 部長 (00180373)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1998: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1997: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Keywords | ホメオボックス遺伝子 / Hox / Meis / Pbx / 骨髄性白血病 / NUP98 / PMX1 / 転写因子 / 分化 / nucleoporin |
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| Research Abstract |
Recent studies have shown that homeobox genes play an important role in hematopoiesis and leukemogenesis. In this project we focused on hox genes, their co-factors Meis and Pbx, and chime homeobox genes identified in human leukemia. The followings were the results of this three-year project.
1. Expression of Hoxa7, Hoxa9, Hoxb8, Meis1 and Meis2 is downreglated during myeloid differentiation of 32Dc13 cells. When these homeobox genes were introduced and stably expressed in 32D cells, myeloid differentiation was blocked. These results suggested that abnormal expression of homeobox genes might affect regulation of hematopoietic cell differentiation.
2. The Meis target sequence was identified. The study clarified that Meis and Pbx cooperatively bin DNA, and that Meis can interact with the Pbx-Hox-DNA complex.
3. We discovered that NUP98 fuses with PMX1 in human AML with chromosome translocation t(1;11)(q23;p15). The chimerical NUP98-PMX1 protein showed structural similarity with NUP98- HOXA9. There is a transcription activation domain in the N-terminal area of NUP98, and both NUP98-HOXA9 and NUP98-PMX1 act as a transcription activator. These chimerical proteins were located not in the nuclear pore but in the nuclear matrix.
4. We generated transgenic mice bearing homeobox genes under the control of the cathepsin G promoter that is specific for myeloid cells. Myeloid leukemia developed in a few NUP98-HOXAI transgenic mice.
5. The novel system to identify target genes of homeobox proteins was devised. Homeobox protein/DNA complexes were purified using anti-Hox antibodies, and the Hox-bound DNA fragments were cloned into the GFP expression vector to make a target sequence library. The library was transiently transfected into appropriate mammalian cells with a Hox expression plasmic. We found that Irak-m is a Hoxa9 target gene in myeloid cells.
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