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


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-1(Δ/Δ)) mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts (PLFs) were remarkably resistant to H(2)O(2)- and diquat-induced cell death, compared to their wild-type (Fra-1(+/+)) counterparts. Fra-1 deficiency ablated oxidant-induced mitochondrion-dependent apoptosis. Fra-1(Δ/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-1(Δ/Δ) cells. Thus, Fra-1 appears to increase susceptibility to oxidants and promotes cell death by attenuating Nrf2-driven antioxidant responses.

DOI: 10.1128/MCB.06390-11
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@article{Vaz2012OxidantinducedCD, title={Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1.}, author={Michelle Rossana Ferreira Vaz and Narsa Machireddy and Ashley Irving and Haranatha R. Potteti and Karinne Chevalier and Dhananjaya V. Kalvakolanu and Sekhar P. M. Reddy}, journal={Molecular and cellular biology}, year={2012}, volume={32 9}, pages={1694-709} }