Regulation of Antioxidant Genes and Oxidative Stress

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DESCRIPTION (provided by applicant): Iron is an essential element by serving as a constituent of vital cellular proteins involved in a variety of cellular functions; however, excess iron is detrimental because it catalyzes formation of reactive oxygen species (ROS). Disorder of iron homeostasis involving iron deficiency or overload is associated with various human health problems such as neurodegenerative disease, cancer and aging. Fine-tuning of intracellular iron levels is therefore essential for maintaining normal cellular function and physiological metabolic balance. Ferritin is the major iron-storage protein in eukaryotic cells and it plays a crucial role in regulation of iron metabolism by detoxifying and storing intracellular excess iron in a non-toxic but bioavailable form. Ferritin synthesis is regulated at both transcriptional and translational levels. Translational regulatory mechanism of ferritin by iron has been extensively studied and well characterized. In contrast, iron-independent transcriptional regulation of the ferritin gene under such conditions as cells need to limit iron availability remains incompletely understood. In particular, little is known about ferritin transcriptional regulation through chromatin remodeling mechanism under oxidative stress conditions. Transcription of ferritin and a battery of antioxidant genes are regulated by a conserved enhancer, termed the ARE (antioxidant responsive element). We hypothesize that chromatin remodeling and associated factors we have recently identified on the human ferritin ARE can serve as crucial proteins that regulate ferritin transcription and iron homeostasis. The proposed experiments will focus on characterization of these new ARE-interacting proteins and their roles in chromatin modifications adjacent to ARE-regulated ferritin and antioxidant genes. The scientific impact of this research will be broad and significant because it will not only provide new insight into the basic transcriptional mechanism of a group of antioxidant genes via coordinated regulation of transcription factors and chromatin-remodeling factors, but also define new regulatory proteins responsible for cellular antioxidant response and iron homeostasis under oxidative stress conditions that are associated with various iron- and ROS-involving human diseases. PUBLIC HEALTH RELEVANCE: Oxidative stress is implicated in various disease states including cancer, neurodegeneration (such as Parkinson's and Alzheimer diseases), and aging. Cellular antioxidant genes play crucial roles in prevention and alleviation of these diseases; however, the regulatory mechanism of cellular antioxidant genes remains incompletely understood. This proposal will provide new insight into antioxidant gene regulation that is crucial for our understanding of the pathogenesis of oxidative stress related disease. In particular, disorder of iron metabolism causing iron overload is potentially toxic to the cells due to the catalytic role of iron in formation of reactive oxygen species (ROS). Thus, the tight regulation of intracellular antioxidant genes and iron levels is crucial to maintaining normal cellular function and prevention of excess ROS production and oxidative stress. This research proposal will elucidate the molecular mechanism through which oxidant- and iron-induced toxicity is alleviated in cells and tissues by investigating the regulation of major iron storage protein, ferritin. This proposal will also investigate the common regulatory mechanism of ferritin and other antioxidant genes that are involved in cellular defense mechanisms against oxidative stress.