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

Michelle Vaz1, Narsa Machireddy, Ashley Irving

  • 1Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Molecular and Cellular Biology
|March 7, 2012
PubMed

Insights

Fra-1 deficiency protects against oxidative stress by enhancing antioxidant responses. Loss of Fra-1 increases glutathione and Nrf2 activity, making cells resistant to oxidant-induced cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Activating Protein-1 (AP-1) transcription factors, including Jun/Fos, are crucial in regulating biological processes such as cell death.
  • Oxidative stress is implicated in numerous diseases and cellular damage pathways.

Purpose of the Study:

  • To investigate the novel role of Fra-1 in oxidant-induced cell death.
  • To elucidate the mechanisms by which Fra-1 influences antioxidant gene expression and cellular response to oxidants.

Main Methods:

  • Utilized Fra-1-deficient (Fra-1(Δ/Δ)) and wild-type (Fra-1(+/+)) mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts (PLFs).
  • Assessed cell death induced by hydrogen peroxide (H(2)O(2)) and diquat.
  • Measured antioxidant enzyme levels, intracellular glutathione (GSH), Nrf2 protein half-life and promoter recruitment, and gene expression via RNA interference (RNAi).

Main Results:

  • Fra-1(Δ/Δ) cells exhibited significant resistance to H(2)O(2)- and diquat-induced cell death.
  • Fra-1 deficiency prevented oxidant-induced mitochondrion-dependent apoptosis.
  • Loss of Fra-1 resulted in elevated basal and stimulated antioxidant enzyme levels and intracellular GSH.
  • Fra-1 deficiency increased Nrf2 half-life, promoter recruitment, and expression of its target antioxidant genes (Nqo1, Hmox1).
  • Restoration of cell death was observed upon GSH depletion or Nrf2/target gene knockdown in Fra-1(Δ/Δ) cells.

Conclusions:

  • Fra-1 promotes susceptibility to oxidant-induced cell death.
  • Fra-1 attenuates the Nrf2-driven antioxidant response pathway.
  • Modulating Fra-1 levels could be a therapeutic strategy for conditions involving oxidative stress.

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