Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila.
Keap1/Nrf2 signaling defends organisms against the detrimental effects of oxidative stress and has been suggested to abate its consequences, including aging-associated diseases like neurodegeneration, chronic inflammation, and cancer. Nrf2 is a prominent target for drug discovery, and Nrf2-activating agents are in clinical trials for cancer chemoprevention. However, aberrant activation of Nrf2 by keap1 somatic mutations may contribute to carcinogenesis and promote resistance to chemotherapy. To evaluate potential functions of Keap1 and Nrf2 for organismal homeostasis, we characterized the pathway in Drosophila. We demonstrate that Keap1/Nrf2 signaling in the fruit fly is activated by oxidants, induces antioxidant and detoxification responses, and confers increased tolerance to oxidative stress. Importantly, keap1 loss-of-function mutations extend the lifespan of Drosophila males, supporting a role for Nrf2 signaling in the regulation of longevity. Interestingly, cancer chemopreventive drugs potently stimulate Drosophila Nrf2 activity, suggesting the fruit fly as an experimental system to identify and characterize such agents.
Sykiotis
Gerasimos P
GP
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Bohmann
Dirk
D
D000375:Aging / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D008017:Life Expectancy; D008297:Male; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity; D015398:Signal Transduction; D015533:Transcriptional Activation
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D010269:Paraquat