Journal
DEVELOPMENTAL CELL
Volume 14, Issue 1, Pages 76-85Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2007.12.002
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Funding
- NCI NIH HHS [R03 CA123591, R03 CA123591-01, R03 CA123591-02] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R03CA123591] Funding Source: NIH RePORTER
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Keapl/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 Keapl/Nrf2 signaling in the fruit fly is activated by oxidants, induces antioxidant and detoxification responses, and confers increased tolerance to oxidative stress. Importantly, keap 1 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 Drosophfila Nrf2 activity, suggesting the fruit fly as an experimental system to identify and characterize such agents.
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