| Project/Area Number |
11138264
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas (A)
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| Allocation Type | Single-year Grants |
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| Research Institution | NATIONAL CANCER CENTER RESEARCH INSTITUTE |
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Principal Investigator |
KITABAYASHI Kazuo NATIONAL CANCER CENTER RES.INST., SECTION HEAD, 放射線研究部, 室長 (20261175)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMIZU Kimiko NATIONAL CANCER CENTER RES.INST., SENIOR RESEARCHER, 放射線研究部, 主任研究官 (00161414)
MOROHOSHI Fumiko NATIONAL CANCER CENTER RES.INST., RESEARCHER, 放射線研究部, 研究員 (20157944)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | leukemia / histone acetylation / cell differentiation / transcription factor / chromosome translocation |
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| Research Abstract |
The AML1-CBFβ transcription factor complex is the most frequent target of chromosomal rearrangements in human leukemia. In the t (8 ; 21) translocation associated with acute myeloid leukemia, the AML1 gene is juxtaposed to the MTG8 gene. We show that the resultant AML1-MTG8 gene product specifically and strongly interacts with a 85 kDa phosphoprotein. Molecular cloning of cDNA indicated that the AML1-MTG8-binding proteins (MTGR1 and MTG16) are highly related to MTG8 and similar to the Drosophila Nervy. Comparison of amino acid sequences among MTGR1, MTG8 and Nervy revealed four evolutionarily conserved regions (NHR1-NHR4). Ectopic expression of AML1-MTG8 in L-G murine myeloid progenitor cells inhibits differentiation to mature neutrophils and induces cell proliferation in response to G-CSF.Analysis with C-terminal deletion mutants of AML1-MTG8 indicated that the region of 51 residues (488 to 538), which contains NHR2, is essential for the induction of G-CSF-dependent cell proliferation
… More
. Immunoprecipitation analysis indicates that this region is required for AML1-MTG8 to form a stable complex with MTGR1. Overexpression of MTGR1 stimulates AML1-MTG8 to induce G-CSF-dependent proliferation of L-G cells and to interfere with AML1-dependent transcription. These results suggest that AML1-MTG8 could function as a complex with MTGR1, and that the complex might be important in promoting leukemogenesis. The normal AML1 proteins reverses the inhibition of cell differentiation by AML1-MTG8 and restores the competence to differentiate. Immunoprecipitation analysis shows that p300 and CBP interact with AML1. The C-terminal region of AML1 is responsible for the induction of cell differentiation and for the interaction with p300. Overexpression of p300 stimulates AML1-dependent transcription and the induction of cell differentiation. These results suggest that p300 plays critical roles in AML1-dependent transcription during the differentiation of myeloid cells. We also found that the MOZ gene is fused to the p300 gene in a t(8 ; 22) translocation associated with acute myeloid leukemia, resulted in expression of a MOZ-p300 fusion acetyltransferase. Less
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