One of the consequences of eukaryotic evolution is the continuous production of reactive oxygen intermediates (ROIs) as a side product of electron transfer reactions. ROIs are highly damaging to biological structures such as lipids, DNA and proteins. Therefore, the regulation of ROI homeostasis is finely controlled. ROI homeostasis can be altered environmentally by conditions such as UV light exposure to produce oxidative stress, or exposure to antioxidants creating hypoxia. Similarly, naturally occurring conditions such as cytokine stimulation induce ROI production, while others such as tissue injury-induced ischemia produce hypoxia. Thus, mammalian cells are exposed to conditions that create both oxidative and hypoxic stress, which results in a broad range of genetic responses has evolved to protect the cell from damage or death. Because of the central role of ROI homeostasis in the maintenance of cellular integrity and function, considerable evidence has accumulated on the role of oxidative stress in the promotion of cellular aging, tumor promotion and possibly atherosclerosis. Similarly, cell culture and animal models have demonstrated important effects of antioxidants and antioxidant vitamins on these processes. Therefore, a definition of the mechanisms by which oxidants and antioxidants control genes involved in ROI homeostasis should lead to new insights on cellular and organismal maintenance. Oxidative stress induces both genes and gene products which counteract ROIs (superoxide dismutase, peroxidase) and ROI-induced damage (glutathione transferases). Intriguingly, hypoxia also induces many of these same enzymes (i.e. glutathione transferase). The likely physiological reason for these seemingly contradictory responses is that a major danger to hypoxic tissue is oxidative damage induced by reoxygenation. Thus it would be highly advantageous for cellular survival to have genes encoding antioxidative enzymes induced under hypoxia to alleviate damage following reoxygenation. Using the glutathione S-transferase (GST) Ya gene as a model for oxidant/antioxidant regulation of gene expression, we have shown that the gene contains tandem AP-1 response elements involved in the response to oxidative stress and antioxidants. Furthermore, we have demonstrated a central role for the proto-oncogene c-jun (a component of the AP- l transcription factor) in cell culture and in vivo. We propose a model in which the c-jun protein is regulated by oxidative stress and antioxidants through separate signalling pathways. This model will be tested by experiments which define the protein factors that mediate oxidant and antioxidant signalling.
