Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 88, Issue -, Pages 93-100Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.06.006
Keywords
Nrf2; Keap1; Stress response; Carcinogenesis; Chemical inducers; Free radicals
Funding
- MEXT/JSPS KAKENHI [24249015, 26460354, 25112502, 2611010]
- CREST, JST
- P-DIRECT, MEXT
- Naito Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [25112502, 26111002] Funding Source: KAKEN
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Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1-Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1-Nrf2 system serves as a potent regulator of our health and disease. (C) 2015 Published by Elsevier Inc.
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