Consumption of some natural compounds, such as sulforaphane, induces a group of detoxifying and antioxidant enzymes, which offer protection against chemical carcinogenesis. Nrf2 (NF-E2 related factor 2), a basic leucine zipper transcription factor, has emerged as a key player in the activation of a variety of detoxifying enzyme genes by binding to the antioxidant response element (ARE) which is located in their promoter regions. Evidence is also accumulating to indicate that induction of Nrf2 proteins and their subsequent nuclear translocation is responsible for the induction of detoxifying enzymes by some chemopreventive agents including sulforaphane. However, the molecular mechanisms by which Nrf2 protein level is induced by chemopreventive agents remain to be investigated. Recent progress in our laboratory leads us to hypothesize that chemopreventive agents, like sulforaphane, induce Nrf2 protein level by enhancing Nrf2 translation through RNA binding proteins and mTOR-dependent pathway, as well as by stabilizing Nrf2 protein through MAPK-mediated phosphorylation. The following aims are designed to test this hypothesis. 1) To determine the signaling molecules which regulate translational activation of Nrf2 by sulforaphane.
This aim will exam the roles of 5' untranslated region (5'UTR) of Nrf2 mRNA and its binding proteins in sulforaphane-induced Nrf2 translation, and will also investigate the roles of mTOR signaling and its downstream effectors, eukaryotic translation factor (elF)-4E binding protein 1 (4E-BP1) and S6 kinase (p70S6K) in translational activation of Nrf2 by sulforaphane. 2) To determine the role of MAPKdependent phosphorylation in sulforaphane-induced stabilization of Nrf2 protein. In this aim, a series of studies will be initiated to identify the MAPK-dependent phosphorylation sites in Nrf2, and to determine the roles of such phosphorylation on Nrf2 protein stability. 3) To determine the in vivo roles of mTOR and MAPK pathways in regulation of Nrf2 induction by sulforaphane in mouse liver. In this aim, experiments will be conducted to exam activation of mTOR and MAPK pathways in sulforaphane-treated mouse liver, and will then test the effects of their inhibition on induction of Nrf2 protein by sulforaphane. A long-term objective of this project is to understand the molecular mechanisms by which dietary agents, like sulforaphane, induce phase 2 detoxifying enzymes. This may aid the identification of additional proteins as molecular targets for future chemopreventive intervention.
| Hu, Rong; Saw, Constance Lay-Lay; Yu, Rong et al. (2010) Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid Redox Signal 13:1679-98 |
