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Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation.

Nrf2 regulates expression of genes encoding enzymes with antioxidant (e.g. heme oxygenase-1 (HO-1)) or xenobiotic detoxification (e.g. NAD(P)H:quinone oxidoreductase, glutathione S-transferase) functions via the stress- or antioxidant-response elements (StRE/ARE). Nrf2 heterodimerizes with small Maf proteins, but the role of such dimers in gene induction is controversial, and other partners may exist. By using the yeast two-hybrid assay, we identified activating transcription factor (ATF) 4 as a potential Nrf2-interacting protein. Association between Nrf2 and ATF4 in mammalian cells was confirmed by co-immunoprecipitation and mammalian two-hybrid assays. Furthermore, Nrf2.ATF4 dimers bound to an StRE sequence from the ho-1 gene. CdCl(2), a potent inducer of HO-1, increased expression of ATF4 in mouse hepatoma cells, and detectable induction of ATF4 protein preceded that of HO-1 (30 min versus 2 h). A dominant-negative mutant of ATF4 inhibited basal and CdCl(2)-stimulated expression of a StRE-dependent/luciferase fusion construct (pE1-luc) in hepatoma cells but only basal expression in mammary epithelial MCF-7 cells. A dominant mutant of Nrf2 was equally inhibitory in both cell types in the presence or absence of CdCl(2). These results indicate that ATF4 regulates basal and CdCl(2)-induced expression of the ho-1 gene in a cell-specific manner and possibly in a complex with Nrf2.

Pubmed ID: 11274184


  • He CH
  • Gong P
  • Hu B
  • Stewart D
  • Choi ME
  • Choi AM
  • Alam J


The Journal of biological chemistry

Publication Data

June 15, 2001

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI-42365
  • Agency: NIDDK NIH HHS, Id: DK-43135
  • Agency: NHLBI NIH HHS, Id: HL-55330
  • Agency: NHLBI NIH HHS, Id: HL-60234

Mesh Terms

  • Activating Transcription Factor 3
  • Activating Transcription Factor 4
  • Amino Acid Sequence
  • Animals
  • Breast
  • Cadmium Chloride
  • Cell Line
  • Cloning, Molecular
  • Conserved Sequence
  • DNA-Binding Proteins
  • Dimerization
  • Epithelial Cells
  • Female
  • Gene Expression Regulation
  • Gene Expression Regulation, Enzymologic
  • Genes, Reporter
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Humans
  • Leucine Zippers
  • Liver Neoplasms, Experimental
  • Membrane Proteins
  • Mice
  • Molecular Sequence Data
  • NF-E2-Related Factor 2
  • Rats
  • Recombinant Proteins
  • Saccharomyces cerevisiae
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured