| Project/Area Number |
15208010
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied biochemistry
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| Research Institution | RIKEN |
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Principal Investigator |
YOSHIDA Minoru RIKEN, Chemical Genetics Laboratory, Director (80191617)
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| Co-Investigator(Kenkyū-buntansha) |
YASHIRODA Yoko RIKEN, Chemical Genetics Laboratory, Researcher (60360658)
YOSHIDA Yukiko Tokyo Metropolitan Organization for Medical Research, 東京都臨床医学総合研究所, Researcher (90271543)
KAMEMURA Kazuo Nagahama Institute of Bio-Science & Technology, Department of Bio-Science, Lecturer (00399437)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥43,290,000 (Direct Cost: ¥33,300,000、Indirect Cost: ¥9,990,000)
Fiscal Year 2005: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2004: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2003: ¥20,930,000 (Direct Cost: ¥16,100,000、Indirect Cost: ¥4,830,000)
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| Keywords | HDAC / Trichostatin A / transcription / Hsp90 / SIRT / CBP / Hsp90 / PKC / PML body / SUMO |
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| Research Abstract |
Among the histone deacetylase (HDAC) enzymes, molecular functions of HDAC4, which localizes in the HDAC4/Bach2 body, and HDAC6, which localizes in the cytoplasm and deacetylates tubulin, were studied. As a result, we found that HDAC4, as well as Bach2, relocalized to the nucleus in response to oxidative stress, and accumulated in the punctate structures that surround the PML bodies. The transcription labeling experiments revealed that the nuclear regions in and around the PML bodies surrounded by HDAC4/Bach2 were transcriptionally inactivated. In the case of HDAC6, we showed that HDAC6 expression repressed the endocytosis of both EGF receptor and transferrin receptor. In the lung cancer cells stably expressing siRNA for the knock down of HDAC6, EGF-induced EGF receptor endocytosis was greatly enhanced thereby down-regulating the level of EGF receptor. However, these cells can grow by compensating the EGF signaling by overexpression of the downstream ERK. These results indicate that HDAC6 regulates the signaling pathways of receptor tyrosine kinases by controlling endocytosis. Furthermore, we searched for novel acetylated proteins using specific HDAC inhibitors, and identified several proteins including Hsp90, SV40 large T-antigen, and poly(A) polymerase (PAP). We also identified more than ten proteins that are acetylated in the fission yeast cells. The functional analysis demonstrated that acetylation caused a decrease in the activity of Hsp90, destabilized the SV40 large T-antigen, and suppressed the nuclear import of PAP. These findings imply that acetylation occurs on a wide variety of cellular proteins and profoundly regulates the protein function.
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