title: Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.
abstract: Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes, both 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 GM02063 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 (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES 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.
authors.affiliation: Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Shusuke
authors.initials: S
authors.lastname: Hira
authors.forename: Jiying
authors.initials: J
authors.lastname: Sun
authors.forename: Chikara
authors.initials: C
authors.lastname: Yamazaki
authors.forename: Yukari
authors.initials: Y
authors.lastname: Zenke
authors.forename: Masao
authors.initials: M
authors.lastname: Ikeda-Saito
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000409:Alanine / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D050981:Erythroid-Specific DNA-Binding Factors; D004926:Escherichia coli / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005914:Globins / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D028884:Karyopherins / Q000378:metabolism*; D016350:Leucine Zippers; D050985:MafK Transcription Factor; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013053:Spectrophotometry; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016335:Zinc Fingers; D000097606:Exportin 1 Protein
chemical_list: D000409:Alanine; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051856:Fanconi Anemia Complementation Group Proteins; D005914:Globins; D005982:Glutathione Transferase; D049452:Green Fluorescent Proteins; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006427:Hemin; D028884:Karyopherins; D050985:MafK Transcription Factor; D008565:Membrane Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C102108:BACH1 protein, human; C494695:MAFK protein, human; C496541:HMOX1 protein, human