Transforming growth factor-β induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene

J Biol Chem. 2013 Jul 12;288(28):20658-67. doi: 10.1074/jbc.M113.450478. Epub 2013 Jun 4.

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.

Keywords: Cancer; Cancer Prevention; Heme Oxygenase; Nrf2; Oxidative Stress; Transcriptional Regulation; Transforming Growth Factor β (TGFβ).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Line
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Fanconi Anemia Complementation Group Proteins / metabolism
  • Gene Expression Regulation / drug effects*
  • HEK293 Cells
  • Heme Oxygenase-1 / genetics*
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Hydroquinones / pharmacology
  • Immunoblotting
  • MafK Transcription Factor / genetics*
  • MafK Transcription Factor / metabolism
  • Microscopy, Fluorescence
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Antioxidants
  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Fanconi Anemia Complementation Group Proteins
  • Hydroquinones
  • MafK Transcription Factor
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Smad Proteins
  • Transforming Growth Factor beta
  • 2-tert-butylhydroquinone
  • Heme Oxygenase-1