title: Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene.
abstract: Transforming growth factor-β (TGF-β) has multiple functions in embryogenesis, adult homeostasis, tissue repair, and development of cancer. Here, we report that TGF-β suppresses the transcriptional activation of the heme oxygenase-1 (HO-1) gene, which is implicated in protection against oxidative injury and lung carcinogenesis. HO-1 is a target of the oxidative stress-responsive transcription factor Nrf2. TGF-β did not affect the stabilization or nuclear accumulation of Nrf2 after stimulation with electrophiles. Instead, TGF-β induced expression of transcription factors MafK and Bach1. Enhanced expression of either MafK or Bach1 was enough to suppress the electrophile-inducible expression of HO-1 even in the presence of accumulated Nrf2 in the nucleus. Knockdown of MafK and Bach1 by siRNA abolished TGF-β-dependent suppression of HO-1. Furthermore, chromatin immunoprecipitation assays revealed that Nrf2 substitutes for Bach1 at the antioxidant response elements (E1 and E2), which are responsible for the induction of HO-1 in response to oxidative stress. On the other hand, pretreatment with TGF-β suppressed binding of Nrf2 to both E1 and E2 but marginally increased the binding of MafK to E2 together with Smads. As TGF-β is activated after tissue injury and in the process of cancer development, these findings suggest a novel mechanism by which damaged tissue becomes vulnerable to oxidative stress and xenobiotics.
authors.affiliation: Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Okita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ogami
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kato
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D015151:Immunoblotting; D050985:MafK Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D006873:Hydroquinones; D050985:MafK Transcription Factor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C018855:2-tert-butylhydroquinone; D051547:Heme Oxygenase-1
keywords: Cancer; Cancer Prevention; Heme Oxygenase; Nrf2; Oxidative Stress; Transcriptional Regulation; Transforming Growth Factor β (TGFβ)