| Redox signaling is a mechanism that facilitates homeostasis during redox insult resulting from cellular respiration, defense, and inflammation. Cellular perception of, and adaptation to redox stress requires a stratified response mediated by key regulatory proteins that utilize cysteine residues as redox switches in response to a broad range of inorganic and organic oxidants and electrophiles. Lipid peroxidation and metabolism are major sources of endogenous reactive oxygen-lipid species and reactive carbonyl species which act on membrane, nuclear, and cytosolic proteins to elicit changes in cell signaling and gene expression. Cyclooxygenase and lipoxygenase metabolism of arachidonic acid leads to the formation of these reactive lipid species, yet very little is known about how these enzymes might govern cellular redox processes. This dissertation provides biochemical and biological evidence demonstrating how cyclooxygenase- and lipoxygenase-derived lipid hydroperoxides (oxidants) and alpha,beta-unsaturated carbonyls (electrophiles) function as redox signaling mediators.;Specifically, Chapter 2 demonstrates how lipid hydroperoxides over-oxidize the conserved catalytic cysteine residues of peroxiredoxins, leading to their inactivation. Peroxiredoxins play a central role in redox signaling due to their dual activity as antioxidants and as sentinel redox switches that govern H2O2-driven cell signaling. Therefore, this research suggests that cyclooxygenase and lipoxygenase activity couples with PRX-dependant mechanisms to modulate biological processes outside of known G-protein coupled signaling.;Chapter 3 shows how alpha,beta-unsaturated carbonyls can carbonylate and antagonize a subset of histone deacetylases which are critical components of chromatin remodeling complexes. In conjunction with the known effects of alpha,beta-unsaturated compounds on transcription factors, these results suggest a novel mechanism by which redox species are able to coordinately govern transcriptional activity and DNA binding capability.;Taken together, this dissertation provides a framework for understanding how normal pathological process, such as inflammation, couple with redox signaling to fully exert a response and how dysregulation of this conjoined activity can promote various disease states. |
