One of the most prominent strategies of cancer chemoprevention might be protecting cells or tissues against various endo- and exogenous carcinogens and carcinogenic metabolites. This protection could be achieved through the induction of phase 2 detoxifying enzymes and antioxidant enzymes, a process mediated mainly by the antioxidant response elements (ARE) located in the promoter of these genes. Our previous application entitled """"""""Regulation of Phase 2 Genes by Chemopreventive Agent BHA"""""""" focused on the early signaling events leading to the induction of phase 2 detoxifying enzymes. Our results demonstrated that the mitogen-activated protein kinase (MARK) and the nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factors, play important roles in ARE-mediated gene expression. Multiple functional motifs have been identified in Nrf2 to elicit the antioxidant response. The activation of Nrf2 signaling appears to be a multiple-step process. Under unstimulated condition, Nrf2 per se can maintain a cytosolic sequestration, which may be further strengthened by the interaction with an actin-binding protein, Kelch-like ECH associating protein 1 (Keapl). Upon exposure to oxidative stress or treatments of Chemopreventive agents, Nrf2 dissociates from Keapl, translocates to the nucleus, binds to the AREs and transactivates phase 2 detoxifying and antioxidant genes. In this renewal application entitled """"""""Chemopreventive Functional Analysis of Nrf2"""""""", we will focus on the molecular mechanisms of Nrf2 signaling by testing the hypothesis that Nrf2 functions as a sensor for diverse dietary Chemopreventive compounds and regulator of cancer chemoprotective genes expression. We will examine the releasing mechanism of Nrf2 from cytosolic sequestration of Keapl by various dietary cancer Chemopreventive compounds, mechanism that govern the nuclear translocation of Nrf2, as well as the mechanisms regulating Nrf2 nuclear retention and transactivation. The results of these investigations will provide fundamental knowledge for our understanding of the molecular mechanisms of Nrf2 signaling as well as for better designing of Nrf2 targeted drugs and cancer Chemopreventive agents, which is one of our long-term goals.
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