Cancer cells display aberrant metabolism, altered antioxidant profiles, and ROS imbalances that may contribute to unregulated growth. Generation of reactive oxygen species (ROS) in living cells is a consequence of normal aerobic metabolism. As such, normal cells have learned to use these various reactive species as indicators of changes in metabolism that may require compensatory changes in gene expression to accommodate the new environment. ROS have the potential to act as mediators of signal transduction at various points along the signal transduction pathway from receptors to transcription factors. Activator protein-2 (AP-2) is an eukaryotic transcriptional regulating factor that can be activated in cells by a variety of physiological and environmental stimuli. AP-2 response elements exist in the genetic regulatory elements of many primary antioxidant enzyme, stress response, and cancer related genes whose expression is activated by UV light and singlet oxygen. Activation of AP-2 and its downstream targets by singlet oxygen may constitute part of a cellular defense mechanism against cytotoxicity caused by anticancer therapies. Our preliminary findings indicate that the AP-2 protein is capable of reversible inhibition of DNA binding depending on its redox status. It will be important to understand the role of AP-2 in normal and cancer cells after exposure to oxidative stress so that its activity can be modulated in the direction necessary for the most favorable therapeutic outcome. The differences in AP-2 regulation between normal and cancer cells are potential targets for cancer therapy. This proposal seeks to test the hypothesis that changes in cellular gene expression brought about by exposure to various types of oxidative stress is due, at least in part, to activation of transcription factor AP-2. To test this hypothesis we will pursue the following specific aims: 1) determine whether activation of AP-2 DNA binding and transactivating activity is induced in normal and transformed human keratinocytes exposed to treatments generating singlet oxygen; 2) test the hypothesis that oxidized membrane lipid components may be involved in signal transduction leading to AP-2 transactivation; 3) determine whether activation of AP-2 is necessary and sufficient for ROS mediated signal transduction and gene expression in normal and malignant cells in response to oxidative stress; and 4) determine the role of AP-2 in establishing and maintaining the malignant phenotype in human epidermal keratinocytes.
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