| Project/Area Number |
11470036
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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 |
General medical chemistry
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| Research Institution | The Institute of Physical and Chemical Research (RIKEN) |
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Principal Investigator |
ISHII Shunsuke RIKEN, Molecular Genetics Laboratory, Chief Scientist, 分子遺伝学研究室, 主任研究員 (00124785)
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| Co-Investigator(Kenkyū-buntansha) |
AKIMARU Hiroshi RIKEN, Molecular Genetics Laboratory, Scientist, 分子遺伝学研究室, 先任研究員 (70241247)
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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 |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2000: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1999: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Keywords | C-activator / CBP / Co-repressor / Ski / Histone acetylation |
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| Research Abstract |
The ski gene was originally identified as an oncogene. We have demonstrated that c-ski proto-oncogene product (c-Ski) directly associates with co-repressors N-CoR and mSin3A and forms a complex with histone deacetylase (HDAC). c-Ski acts as a co-repressor, and is required for transcriptional repression mediated by tumor suppressors, Mad and Rb, and nuclear hormone receptors . We have generated the mutant mice lacking the sno (ski-related novel) gene, which encodes the ski-related gene. Sno is essential for blastocyst formation in early development, and the sno-deficient embryos die at an early stage of development. The sno heterozygous mutants appeared to be healthy, but spontaneously arisen tumors were observed in them. Furthermore, they have the increased susceptibility to tumorigenesis when they were treated with the chemical carcinogen DMBA.Similar results were also obtained with the ski heterozygous mutant mice. These results indicate that ski and sno genes act as either oncogene or tumor suppressor depending on the cellular context. We also generated the mutant mice lacking CBP, which is the most famous co-activator containing the histone acetylase activity. The Cbp-deficient embryos died at E12.5-E14.5 due to hemorrhage in the brain. Hemorrhage was caused by impaired formation of blood vessel, indicating the important role of CBP for blood vessel formation. The Cbp-deficient embryos also exhibited the partially impaired hematopoesis in fetal liver. We have found that CBP directly acetylates c-Myb, and acetylation of c-Myb enhances the association between c-Myb and CBP.This is an interesting novel mechanism by which co-activator CBP regulates the activity of transcription factor.
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