Expression regulation of phospholipid hydroperoxide glutathione peroxidase isoforms. Transcriptional and post-transcriptional processes

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12/15-Lipoxygenases (12/15-LOX) and phospholipid hydroperoxide glutathione peroxidase (PH-GPx) are counterplayers in the metabolism of complex lipid hydroperoxides. Among LOXs, 12/15-LOXs are unique with respect to their capability of oxygenating ester lipids and PH-GPx is the only glutathione peroxidase capable of reducing hydroperoxy ester lipids. PH-GPx was identified as endogenous regulator of cellular LOX pathways and recently we found that both enzymes are inversely regulated by cytokines. In this project we intend to investigate the mechanism of the functional interplay of both enzymes on transcriptional, translational and pos-translational levels. For this purpose the following questions will be investigated: 1. Is overexpression of functional 12/15-LOX sufficient to down-regulate PH-GPx expression and does vice versa 12/15-LOX knockout up-regulate PH-GPx expression? 2. Which part of the 5'-flanking region of the murine PH-GPx gene contains the promoter (functional promoter studies) and what potential binding sites for transcription factors identified in the 5'-flanking region are functional? 3. Do interleukins-4 (IL-4) and -13 (IL-13) induce the expression of nuclear proteins capable of binding to the promoter of 12/15-LOX and PH-GPx genes and are these potential transcription factor involved in the inverse regulation of both enzymes?