Multiple lines of evidence point to the existence of cellular defense against xenobiotic chemical stress in mammalian cells. Increased expression of antioxidant and detoxification genes contributes to cell survival. While induction of oxidative stress represents one component in the mechanism of toxicity of many types of xenobiotics, our recent data suggest that induction of Phase II detoxification pathway dominates the gene expression network of oxidants. A master switch controlling the expression of Phase II antioxidant and detoxification enzymes is the transcription factor Nrf2. We found that oxidants cause rapid translation of endogenous Nrf2 protein. Little is known about the selectivity and mechanisms of protein translation under oxidative stress. We hypothesize that """"""""IRES mediates oxidant induced selective translation of Nrf2 protein"""""""".
The Specific Aims i nclude 1). Test that oxidants turn on Nrf2 protein translation due to Internal Ribosomal Entry Site (IRES) in the 5'UTR;2). Apply proteomic technology to address the mechanism of stress induced protein translation by identifying the proteins bound to Nrf2 5'UTR. Cell survival represents a critical layer of defense against chemical toxicity. Therefore studying the mechanism of stress induced protein translation is an imperative task for understanding the etiology of diseases associated with chemical exposure.
This proposal plans to study the mechanism of oxidative stress induced Nrf2 protein translation.
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