Partially reduced oxygen species are reactive derivatives of molecular oxygen well characterized to participate in cellular responses generally classified as oxidative stress. While the focus in the past has been on the role of reactive oxygen species (ROS) in toxicity and disease mechanisms, it has become increasingly clear that these molecules are powerful signaling molecules employed in normal cell growth and survival. The outcome of exposure/production of ROS depends on concentration and time course such that high, bolus exposure leads to toxicity (apoptosis or necrosis) while low continuous exposure enhances cell survival and stimulates growth. Recently several lines of evidence suggest that ROS produced by NAD(P)H oxidases (NOX) function in initiation and regulation of cell signaling pathways. For example, a NOX isoform appears to be activated by receptor tyrosine kinases (EGFR, PDGF, IR) leading to H202 production and increased phosphorylation of the receptor and enhanced signaling, inhibition of NOX activity in melanoma cells by antisense to NOX4 or p22phox leads to growth inhibition, and expression of NOX1 in fibroblasts leads to a transformed phenotype and tumor formation when these cells are injected in a mouse model. Further, elevated NOX expression is associated with smooth muscle cell proliferation and commonly seen in cells derived from human cancers. The mechanism through which NOX isoforms regulate growth and survival are not known. However, studies with exogenously applied H202 would suggest activation of growth and survival (antiapoptotic) signals are important. Thus, in these studies we will test the hypothesis that cellular expression of NOX isoforms regulates growth factor receptor activity and provides antiapoptotic signals leading to cell growth and survival. To accomplish this, we will manipulate NOX levels in cells in culture and determine the effects of altered expression on growth and apoptosis and investigate the underlying cellular mechanisms.
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