| Project/Area Number |
13214069
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Hiroshima Univeisity Graduate School of Biomedical Sciences |
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Principal Investigator |
IGARASHI Kazuhiko Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (00250738)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥38,200,000 (Direct Cost: ¥38,200,000)
Fiscal Year 2004: ¥9,500,000 (Direct Cost: ¥9,500,000)
Fiscal Year 2003: ¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2001: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | Bach1 / Bach2 / transcription factor / apoptosis / B cell / heme / oxidative stress / Maf / AP-1 / 癌 / ストレス / 発癌制御 / 発現制御 / 遺伝子 / 核酸 |
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| Research Abstract |
Several lines of evidence suggest that gene expression is regulated not only by the interaction between transcription factors and DNA but also by the higher order architecture oft the cell nucleus. PML bodies are one of the most prominent nuclear substructures, which have been implicated in transcription regulation during apoptosis and stress responses. Bach2 is a member of the BTB-basic region leucine zipper factor family, and represses transcription activity directed by the 12-0-tetradecanoylphorbol-13-acetate response element, the Maf recognition element and the antioxidant-responsive element. Bach2 forms nuclear foci associated with PML bodies upon oxidative stress and induces apoptosis when overexpressed in NIH3T3 cells and B cell lines. Transcription activity associated with PML bodies is selectively repressed by the recruitment of Bach2 around PML bodies. Fluorescence recovery after photobleaching experiments revealed that Bach2 showed rapid turnover in the nuclear foci. Bach2 N
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terminal region including the BTB domain is essential for the focus formation. SUMOylation of Bach2 is required for the recruitment of the protein around PML bodies.
Bach1 is a transcriptional repressor of heme oxygenase-1 and other heme-related genes some of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild-type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GMO2063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1 whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs were found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated nuclear export signal dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.
By analyzing the proliferation of wild-type and Bach1-knockout smooth muscle cells (SMC) in vitro, we found that Bach1 is involved in the proliferation of SMC. We are currently searching for the down-stream, direct target gene of Bach1 in SMC and fibroblastic cells. Less
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