Specificity of Stress-Responsive Transcription Factors Nrf2, ATF4, and AP-1.
Cellular stress leads to an upregulation of gene transcription. We asked if there is a specificity in the activation of the stress-responsive transcription factors Nrf2, ATF4, and AP-1/c-Jun, or if activation of these proteins is a redundant cellular answer toward extracellular stressors. Here, we show that oxidative stress, induced by stimulation of the cells with the oxidant arsenite, strongly activated gene transcription via the stress-responsive element (StRE), while phorbol ester or tunicamycin, activators of AP-1/c-Jun or ATF4, respectively, activated AP-1 or nutrient-sensing response element-mediated transcription. Preincubation of the cells with N-acetyl-cysteine or overexpression of thioredoxin selectively attenuated arsenite-induced upregulation of StRE-regulated transcription. Expression of either dominant-negative or constitutively active mutants of Nrf2, ATF4, or c-Jun confirmed that distinct transcription units are regulated by these transcription factors. Physiological stimuli involving the activation of either Gαq-coupled designer receptors or the protein kinases c-Jun N-terminal protein kinase or p38 strongly stimulated transcription via AP-1/c-Jun, with minimal effects on Nrf2 or ATF4-responsive promoters. Thus, activation of transcription by extracellular signaling molecules shows specificity at the level of the chemical nature of the signaling molecule, at the level of the intracellular transduction process, and at the level of signal-responsive transcription factors. J. Cell. Biochem. 118: 127-140, 2017. © 2016 Wiley Periodicals, Inc.
Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, Building 44, D-66421, Homburg, Germany.
Oliver G
OG
Rössler
Department of Medical Biochemistry and Molecular Biology, Saarland University Medical Faculty, Building 44, D-66421, Homburg, Germany.
Gerald
G
Thiel
D000111:Acetylcysteine / Q000494:pharmacology; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D018053:Arsenites / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation
C497109:ATF4 protein, human; D018053:Arsenites; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; C015001:arsenite; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine
ARSENITE; ATF4; DESIGNER RECEPTOR; Nrf2; THIOREDOXIN; c-Jun