Regulation of cell proliferation ancl apoptcsis by the nansaiption factois Bach1 and Bach2

• Project/Area Number: 13214069
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hiroshima Univeisity Graduate School of Biomedical Sciences
• 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)
• Project Period (FY): 2001 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥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)
• 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

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 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.

Research Products

• [Journal Article] Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury. (2005)
  • Author(s): Omura, S. 他
  • Journal Title: Genes to Cells 10 Pages: 277-285
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: Genes Cells 10 Pages: 277-285
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury (2005)
  • Author(s): Omura, S.
  • Journal Title: Genes Cells 10 Pages: 277-285
• [Journal Article] Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1 (2005)
  • Author(s): Suzuki H.
  • Journal Title: EMBO J. 23 Pages: 2544-2553
• [Journal Article] The transcriptional programme of antibody class switching involves the repressor Bach2. (2004)
  • Author(s): Muto, A. 他
  • Journal Title: Nature 429 Pages: 566-571
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2. (2004)
  • Author(s): Tashiro, S.他
  • Journal Title: Mol.Cell.Biol. 24 Pages: 3473-3484
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1 (2004)
  • Author(s): Suzuki, H.他
  • Journal Title: EMBO J. 23 Pages: 2544-2553
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: EMBO J. 23 Pages: 2544-2553
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Nature 429 Pages: 566-571
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Mol. Cell. Biol. 24 Pages: 3473-3484
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • 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
• [Journal Article] Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nf2 (2004)
  • Author(s): Kobayashi, A.
  • Journal Title: Mol.Cell.Biol. 24 Pages: 7130-7139
• [Journal Article] The transcriptional programme of antibody class switching involves the repressor Bach2 (2004)
  • Author(s): Muto, A.
  • Journal Title: Nature 429 Pages: 566-571
• [Journal Article] Repression of PML nuclear body-associated transcription by oxidative (2004)
  • Author(s): Tashiro, S.
  • Journal Title: Mol.Cell.Biol. 24 Pages: 3473-3484
• [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.
  • Journal Title: Proc.Natl.Acad.Sci.USA 101 Pages: 1461-1466
• [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.他
  • Journal Title: J.Biol.Chem. 277 Pages: 20724-20733
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. (2002)
  • Author(s): Sun, J.他
  • Journal Title: EMBO J. 21 Pages: 5216-5224
  • Description: 「研究成果報告書概要(和文)」より
• [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.
  • Journal Title: EMBO J. 21 Pages: 5216-5224
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: J.Biol.Chem. 277 Pages: 20724-20733
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: EMBO J. 20 Pages: 2835-2843
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tashiro, S.: "Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2."Mol.Cell.Biol.. in press. (2004)
• [Publications] Sun, J.: "Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network."Proc.Natl.Acad.Sci.USA. 101. 1461-1466 (2004)
• [Publications] Brand, M.: "Dynamic changes in transcription factor complexes during erythroid differentiation revealed by quantitative proteomics."Nature Struct.Mol.Biol.. 11. 73-80 (2004)
• [Publications] Tahara, T.: "Heme positively regulates the expression of b-globin at the locus control region via the transcription factor Bach1 in erythroid cells."J.Biol.Chem.. 279. 5480-5487 (2004)
• [Publications] Suzuki, H.: "Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene."J.Biol.Chem.. 278. 49246-49253 (2003)
• [Publications] Kamio, T.: "The B cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs."Blood. 102. 3317-3322 (2003)
• [Publications] Katsuoka, F.: "Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response."Mol Cell Biol.. 23. 1163-1174 (2003)
• [Publications] Morii, E.: "Interaction and Cooperation of mi Transcription Factor (MITF) and Myc-associated Zinc-finger Protein-related Factor (MAZR) for Transcription of Mouse Mast Cell Protease 6 Gene"J. Biol. Chem.. 277. 8566-8571 (2002)
• [Publications] Muto, A.: "Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apotosis and its interaction with PML nuclear bodies"J. Biol. Chem.. 277. 20724-20733 (2002)
• [Publications] Hoshino, H.: "Expression of the oxidative stress-regulated transcription factor Bach2 in differentiating neuronal cells"J. Biochem.. 132. 427-431 (2002)
• [Publications] Sun, J.: "Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene"EMBO J.. 21. 5216-5224 (2002)
• [Publications] Katsuoka, F.: "Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response"Mol. Cell Biol.. 23. 1163-1174 (2003)
• [Publications] Kitamuro, T.: "Bach 1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells"J. Biol. Chem.. 278. 9125-9133 (2003)
• [Publications] Kanezaki, R.: "Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform"J. Biol. Chem.. 276. 7278-7284 (2001)
• [Publications] Ogawa, K.: "Heme mediates de-repression of Maf recognition element through direct binding to transcription repressor Bach1"EMBOJ.. 20. 2835-2843 (2001)
• [Publications] Leach, K.: "Reconstitution of human b-Globin locus control region hypersensitive sites in the absence of chromatin assembly"Mol. Cell. Biol.. 21. 2629-2640 (2001)
• [Publications] Tanabe, O.: "Fission yeast homologues of the B' subunit of protein phosphatase 2A : multiple roles in mitotic cell division and functional interaction with calcineurin"Genes Cells. 6. 455-474 (2001)
• [Publications] Sun, J.: "Promoter of Mouse Transcription Repressor bach1 Is Regulated by Sp1 and Trans-Activated by Bach1"J. Biochem.. 130. 385-392 (2001)
• [Publications] Sawado, T.: "Activation of b-major globin gene transcription is associated with recruitment of NF-E2 to the b-globin LCR and gene promoter"Proc. Natl. Acad. Sci. U.S.A.. 98. 10226-10231 (2001)