HYDROGEN PEROXIDE ACTIVATION OF THE STAT PATHWAY

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Reactive oxygen species are involved in a variety of diseases including atherosclerosis, adult respiratory distress syndrome, pulmonary fibrosis, and alzheimer's. Reactive oxygen species also have physiological roles and may even function as second messengers in cellular metabolism. Virtually all living organisms have been found to rapidly activate new gene transcription in response to oxidative stress. Some of the genes activated by reactive oxygen are genes involved in detoxifying these species, such as catalase and superoxide dismutase. In mammalian cells several transcription factors that are known to be involved in the regulation of immediate early genes are also activated by reactive oxygen. These include NF Kappa B and the AP-1 complex. Recently a new family of transcription factors, called Stats (for Signal transducers and activators of transcription) has been described that mediates part of the transcriptional response to growth factors and cytokines.. We have found that in fibroblasts, the Stat signal transduction pathway is activated within five minutes of treatment of cells with hydrogen peroxide. The goals of this proposal are to elucidate the mechanisms of activation of the Stat transcription factors by H2O2 and to identify genes regulated by H2O2 via Stat transcription factor activation. The aims of the proposal are 1) to identify the redox regulatory influences on the activation of Stats by reactive oxygen 2) to identify the tyrosine kinases activated by H2O2 responsible for Stat activation and 3) to understand the role of the Stats in the transcriptional response to H2O2.