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- _2 value "Free radicals and other ROS are generated by all aerobic cells and are known to participate in a wide variety of deleterious reactions [1]. A number of studies have also demonstrated that bursts of oxidant production as well as dramatic changes in the activities of various antioxidant defenses are closely associated with alterations in gene expression in a variety of tissues from phylogenetically diverse organisms [1-3]. Free radical reactions have been observed to influence molecular and biochemical processes and to directly cause some of the changes observed in cells during differentiation, aging, and transformation [3-9]. These observations have been interpreted to suggest that cells evolved strategies to utilize ROS as biological stimuli [2,8 -11]. Furthermore, ROS and antioxidants are known to influence the expression of a number of genes and signal transduction pathways [1,12-17] and are thought to act as subcellular messengers for certain growth factors [11,13,18,19]. Indeed, the last decade has seen rapid if not explosive growth in the number of genes shown to be influenced by redox changes as well in as those that exert downstream effects through increased ROS formation. This review article is intended to provide a convenient summary of known redox effects on gene expression. Because nearly half of the effects discussed involve members of the MAP kinase and NF-kB signaling pathways or genes regulated by these pathways, a detailed discussion of these signal transduction pathways is also presented. Although we have intentionally kept our overview brief, we include a short discussion of the various species and tissue-specific differences in redox effects that are known to exist as well a summary of the molecular basis of some of these differences. Cell state transitions leading to transformation, differentiation, and senescence tend to cause large changes in cellular redox state. Our discussion concludes with a brief overview of potential consequences of redox changes for signaling pathways during the cellular transitions. OXIDANTS AND ANTIOXIDANTS MODULATE GENE EXPRESSION A number of genes and cellular pathways are now thought to be regulated by variations in cellular redox status. Identification of redox-sensitive genes and pathways has culminated from a number of independent studies and multiple strategies of detection. Changes in cellular redox state can modulate transcriptional activation of collagen [20] and collagenase [21], post-transcriptional control of ferritin [22,23], and activation of transcription factors such as Myb [24] and Egr-1 [25] as well as the binding activity of the fos/jun (AP-1) protein conjugate [9,26]. Several proto-oncogenes are known to be transcriptionally activated by increased cellular oxidation. For example, exposure of both normal and transformed cells to UV radiation or to H2O2 stimulates increased expression of jun-B, jun-D, c-fos, and fos-B [27-34]. Extensive analysis of this effect by several laboratories has revealed that the influence of H2O2 treatment on c-fos as well as on other early response genes such as c-jun and c-myc is to some extent mediated by PKC [27,29,30,32,35,36]. Presently, the exact sequence of events leading to induction of c-fos transcription after an oxidizing stimulus remains unclear. H2O2 has been used frequently as an oxidative stimulus to identify redox-sensitive genes. For example, Crawford and his colleagues [37-40] used differential display to isolate a number of oxidation-sensitive genes (the so-called 'adapt genes') from hamster fibroblasts treated with H2O2. Although the identity of some of these genes remains unknown, adapt 66 was found to be a homologue of mafG [38], adapt 73 is homologous with a cardiac shock response gene (PigHep3) [41], and adapt 78 is a critical gene associated with Down's syndrome [40]. A specific protein tyrosine-phosphatase has been isolated from H2O2-stimulated human cells..." provenance.
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