| Project/Area Number |
10470063
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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 |
Experimental pathology
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| Research Institution | Sasaki Institute |
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Principal Investigator |
OIKAWA Tsuneyuki Department of Cell Genetics, Sasaki Institute, Head, 細胞遺伝部, 部長 (80150241)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Hitomi Department of Cell Genetics, Sasaki Institute, Research Associate, 細胞遺伝部, 研究員 (30290977)
NEGISHI Fumiko (KIHARA Fumiko) Department of Cell Genetics, Sasaki Institute, Research Associate, 細胞遺伝部, 研究員 (40177902)
YAMADA Toshiyuki Department of Cell Genetics, Sasaki Institute, Chief, 細胞遺伝部, 主任研究員 (20183981)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | leukemia / differentiation / apoptosis / transcription factor / Ets family / oncogene / PU.1 / GATA-1 / CBP / 白血球 / 細胞増殖 / 分化 |
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| Research Abstract |
We previously reported that overexpression of PU.1, a member of ets family oncogenes, induces differentiation inhibition, growth arrest and apoptosis in murine erythroleukemia (MEL) cells treated with dimethylsulfoxide (DMSO) (Blood 89 : 1383-1393, 1997).
In the present study, we have investigated molecular mechanisms of PU-.1-induced effects in MEL cells. Among several apoptosis-related proteins examined, expression of the Bcl-2 and c-Myc protein was significantly suppressed in PU.1-overexpressing MEL cells. Introduction of either bcl-2 or c-myc gene in the cells prevented the apoptosis, suggesting that down-regulation of the bcl-2 and c-myc genes is involved in PU.1-induced apoptosis in MEL cells. Furthermore, the DNA binding activity of GATA-1, an erythroid-specific transcription factor critical for survival of erythroid cells, was markedly reduced in PU.1-overexpressing MEL cells treated with DMSO. By using two-hybrid system, we found that physical and functional interactions between PU.1 and the coactivator CBP(CREB binding protein), suggesting that positive and negative cross-talk between transcription factors through limiting amount of CBP. Indeed, overexpression of c-myb inhibited PU.1-mediated transactivation. PU.1-induced growth arrest and apoptosis but not differentiation inhibition was prevented by overexpression of CBP in MEL cells. Overexpression of PU.1 not only inhibited erythroid differentiation but also promoted myelomonocytic differentiation of MEL cells. We have identified several novel genes associated with overexpression of PU.1 in MEL cells by the method of differential display. We are now cloning the genes to analyze their biological activities.
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