title: Oxidant-induced cell death and Nrf2-dependent antioxidative response are controlled by Fra-1/AP-1.
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-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.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Vaz
authors.forename: Narsa
authors.initials: N
authors.lastname: Machireddy
authors.forename: Ashley
authors.initials: A
authors.lastname: Irving
authors.forename: Haranatha R
authors.initials: HR
authors.lastname: Potteti
authors.forename: Karinne
authors.initials: K
authors.lastname: Chevalier
authors.forename: Dhananjaya
authors.initials: D
authors.lastname: Kalvakolanu
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D051267:NF-E2-Related Factor 2; D016877:Oxidants; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C495636:Nfe2l2 protein, mouse