2004 Fiscal Year Final Research Report Summary
Regulation of cell proliferation ancl apoptcsis by the nansaiption factois Bach1 and Bach2
| 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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| Keywords | Bach1 / Bach2 / transcription factor / apoptosis / B cell / heme / oxidative stress / Maf |
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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
… More
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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[Journal Article] Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury.2005
Author(s)
Omura, S., Suzuki, H., Toyofuku, M., Ozono, R., Kohno, N., Igarashi, K.
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Journal Title
Genes Cells 10
Pages: 277-285
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.2004
Author(s)
Suzuki, H., Tashiro, S., Hira, S., Sun, J., Yamazaki, C., Zenke, Y., Ikeda-Saito, M., Yoshida, M., Igarashi, K.
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Journal Title
EMBO J. 23
Pages: 2544-2553
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The transcriptional programme of antibody class switching involves the repressorBach2.2004
Author(s)
Muto, A., Tashiro, S., Nakajima, O., Hoshino, H., Takahashi, S., Sakoda, E., Ikebe, D., Yamamoto, M., Igarashi, K.
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Journal Title
Nature 429
Pages: 566-571
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2.2004
Author(s)
Tashiro, S., Muto, A., Tanimoto, K., Tsuchiya, H., Suzuki, H., Hoshino, H., Yoshida, M., Walter, J., Igarashi, K.
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Journal Title
Mol. Cell. Biol. 24
Pages: 3473-3484
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network.2004
Author(s)
Sun, J., Brand, M., Zenke, Y., Tashiro, S., Groudine, M., Igarashi, K.
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Journal Title
Proc. Natl. Acad. Sci. USA 101
Pages: 1461-1466
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene.2002
Author(s)
Sun, J., Hoshino, H., Takaku, K., Nakajima, O., Muto, A., Suzuki, H., Tashiro, S., Takahashi, S., Shibahara, S., Alain, J., Taketo, M.M., Yamamoto, M., Igarashi, K.
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Journal Title
EMBO J. 21
Pages: 5216-5224
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with PML nuclear bodies.2002
Author(s)
Muto, A., Tashiro, S., Tsuchiya, H., Kume, A., Kanno, M., Ito, E., Yamamoto, M., Igarashi, K.
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Journal Title
J.Biol.Chem. 277
Pages: 20724-20733
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heme mediates de-repression of Maf recognition element through direct binding to transcription repressor Bach1.2001
Author(s)
Ogawa, K., Sun, J., Taketani, S., Nakajima, O., Nishitani, C., Sassa, S., Hayashi, N., Yamamoto, M., Shibahara, S., Fujita, H., Igarashi, K.
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Journal Title
EMBO J. 20
Pages: 2835-2843
Description
「研究成果報告書概要(欧文)」より
