Protection of cells against reactive oxygen species and xenobiotic electrophiles is a mechanism of cancer chemoprevention. One approach to achieve this outcome is to induce cells to produce more phase 2 detoxification enzymes such as quinone reductase-1, glutathione S-transferase, etc. The Kelch-like ECH-associated protein 1 (Keap1) and its binding partner, transcription factor NF-E2-related factor-2 (Nrf2), are important chemoprevention targets because of their role in regulating the antioxidant response element (ARE) in response to oxidative stress and exposure to xenobiotic electrophiles. Alkylation of the "sensor" protein Keap1 appears to trigger a response resulting in Nrf2 accumulation in the nucleus and ARE activation. Human Keap1 protein contains 27 cysteines, some of which have been identified as targets of electrophiles that, upon alkylation, facilitate Nrf2 accumulation and ARE activation. However, the role of another binding partner of Keap1 and Nrf2, Cullin3-based E3-ligase ubiquitination complex (CUL3), in the activation of the ARE remains unclear and was this subject of this investigation.
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