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

Research output: Contribution to journalArticle

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 1 2012

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Transcription Factor AP-1
Oxidants
Cell Death
Antioxidants
Transcription Factors
Diquat
Fibroblasts
Biological Phenomena
RNA Interference
Glutathione
Half-Life
Mitochondria
Apoptosis
Gene Expression
Lung
Enzymes
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Vaz, M., Machireddy, N., Irving, A., Potteti, H. R., Chevalier, K., Kalvakolanu, D., & Reddy, S. P. (2012). Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. Molecular and Cellular Biology, 32(9), 1694-1709. https://doi.org/10.1128/MCB.06390-11

Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. / Vaz, Michelle; Machireddy, Narsa; Irving, Ashley; Potteti, Haranatha R.; Chevalier, Karinne; Kalvakolanu, Dhananjaya; Reddy, Sekhar P.

In: Molecular and Cellular Biology, Vol. 32, No. 9, 01.05.2012, p. 1694-1709.

Research output: Contribution to journalArticle

Vaz, M, Machireddy, N, Irving, A, Potteti, HR, Chevalier, K, Kalvakolanu, D & Reddy, SP 2012, 'Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1', Molecular and Cellular Biology, vol. 32, no. 9, pp. 1694-1709. https://doi.org/10.1128/MCB.06390-11
Vaz, Michelle ; Machireddy, Narsa ; Irving, Ashley ; Potteti, Haranatha R. ; Chevalier, Karinne ; Kalvakolanu, Dhananjaya ; Reddy, Sekhar P. / Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 9. pp. 1694-1709.
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