Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1

Michelle Vaz, Narsa Machireddy, Ashley Irving, Haranatha R. Potteti, Karinne Chevalier, Dhananjaya Kalvakolanu, Sekhar P. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

AP-1 (Jun/Fos) transcription factors play key roles in various biological processes, including cell death. Here we report a novel role for Fra-1 in oxidant-induced cell death controlled by modulating antioxidant gene expression. Fra-1-deficient (Fra-1Δ/Δ) mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts (PLFs) were remarkably resistant to H2O2-and diquat-induced cell death, compared to their wild-type (Fra-1+/+) counterparts. Fra-1 deficiency ablated oxidant-induced mitochondrion-dependent apoptosis. Fra-1Δ/Δ cells had elevated basal levels of antioxidant enzymes and intracellular glutathione (GSH), which were further stimulated by oxidants. Loss of Fra-1 led to an increased half-life of transcription factor Nrf2 and increased recruitment of this protein to the promoters of antioxidant genes and increased their expression. Depletion of intracellular GSH or RNA interference (RNAi)-mediated knockdown of Nqo1, Hmox1, and Nrf2 restored oxidant-induced cell death in Fra-1δ/Δ cells. Thus, Fra-1 appears to increase susceptibility to oxidants and promotes cell death by attenuating Nrf2-driven antioxidant responses.

Original languageEnglish (US)
Pages (from-to)1694-1709
Number of pages16
JournalMolecular and cellular biology
Volume32
Issue number9
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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