EXCEED THE SPACE PROVIDED. Numerous chemicals have tumor promoting activity by a variety of mechanisms including the production of reactive oxygen species. Excess levels of reactive oxygen could lead to deleterious cellular changes including oxidative DNA damage and altered gene expression. Two members of the CNC-basic-leucine zipper transcription factor family, Nrfl and Nrf2, are expressed at high levels in various organs such as the liver, kidney and muscle. Recent studies suggest the importance of Nrfl and Nrf2 in the oxidative stress response. Fibroblasts derived from mice with targeted deletion of nrfl or nrf2 gene are hypersensitive to the toxic effects of various oxidative-stress-inducing compounds. Genes encoding antioxidants and Phase II detoxification enzymes have been shown to be targets for Nrfl and Nrf2. In addition, we found that genes encoding enzymes involved in glutathione biosynthesis are also transcriptional targets for Nrfl and Nrf2. We postulate that Nrfl and Nrf2 have shared functions in regulating expression of genes that protect cells against the toxic effects of oxidative stress. The long-term goal of our research is to understand the roles of Nrfl and Nrf2 in the cellular response against oxidative stress. The immediate goals within this context will be pursued in the following aims. (1) Determine the extent of functional redundancy between nrfl and nrf2 in promoting cell survival and protecting cells against oxidative stress. (2) Define the structural features of Nrfl and Nrf2 that are important in oxidative stress response to determine potential mechanisms for redundancy. (3) Determine the role of Nrfl and Nrf2 in oncogenesis. (4) Determine the role of Nrfl in the adult mouse using conditional knockouts. The proposed studies to examine the cellular and molecular aspects of CNC-factor knockouts will provide information on the physiologic roles of Nrfl and Nrf2 in anticxidant gene expression and oxidative-stress response. PERFORMANCE SITE ========================================Section End===========================================
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