Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene.
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.
Mesh Terms:
Antioxidants, Basic-Leucine Zipper Transcription Factors, Cell Line, Fanconi Anemia Complementation Group Proteins, Gene Expression Regulation, HEK293 Cells, Heme Oxygenase-1, Humans, Hydroquinones, Immunoblotting, MafK Transcription Factor, Microscopy, Fluorescence, NF-E2-Related Factor 2, Promoter Regions, Genetic, Protein Binding, RNA Interference, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Smad Proteins, Transforming Growth Factor beta
Antioxidants, Basic-Leucine Zipper Transcription Factors, Cell Line, Fanconi Anemia Complementation Group Proteins, Gene Expression Regulation, HEK293 Cells, Heme Oxygenase-1, Humans, Hydroquinones, Immunoblotting, MafK Transcription Factor, Microscopy, Fluorescence, NF-E2-Related Factor 2, Promoter Regions, Genetic, Protein Binding, RNA Interference, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Smad Proteins, Transforming Growth Factor beta
J. Biol. Chem.
Date: Jul. 12, 2013
PubMed ID: 23737527
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