title: Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2.
abstract: A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant-response element), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene regulation.
authors.affiliation: Department of Biotechnology and Molecular Medicine, AI Virtanen Institute for Molecular Sciences, University of Eastern Finland, FIN-70211, Kuopio, Finland.
authors.forename: Henna-Kaisa
authors.initials: HK
authors.lastname: Jyrkkänen
authors.forename: Suvi
authors.initials: S
authors.lastname: Kuosmanen
authors.forename: Merja
authors.initials: M
authors.lastname: Heinäniemi
authors.forename: Heidi
authors.initials: H
authors.lastname: Laitinen
authors.forename: Emilia
authors.initials: E
authors.lastname: Kansanen
authors.forename: Eero
authors.initials: E
authors.lastname: Mella-Aho
authors.forename: Hanna
authors.initials: H
authors.lastname: Leinonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis*; D051856:Fanconi Anemia Complementation Group Proteins / Q000096:biosynthesis*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009574:Nitro Compounds / Q000494:pharmacology; D009829:Oleic Acids / Q000494:pharmacology; D020218:Response Elements / Q000502:physiology*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009574:Nitro Compounds; D009829:Oleic Acids; D013454:Sulfoxides; D013861:Thiocyanates; C016766:sulforaphane