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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094828-07
Application #
7406744
Study Section
Special Emphasis Panel (ZRG1-ONC-W (02))
Program Officer
Crowell, James A
Project Start
2001-06-11
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
7
Fiscal Year
2008
Total Cost
$293,335
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Saw, Constance Lay-Lay; Cintrón, Melvilí; Wu, Tien-Yuan et al. (2011) Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos 32:289-300
Wu, Tien-Yuan; Khor, Tin Oo; Saw, Constance Lay Lay et al. (2011) Anti-inflammatory/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis. AAPS J 13:1-13
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