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All rights reserved. http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAAJaP1mskStE6RFM4v5sJxYHt1CTQ7ZSDDurrYN1NHTc#_4 http://resource.belframework.org/belframework/20131211/knowledge/large_corpus.bel http://purl.org/pav/version 20131211 http://www.tkuhn.ch/bel2nanopub/RAAJaP1mskStE6RFM4v5sJxYHt1CTQ7ZSDDurrYN1NHTc#_3 http://www.w3.org/ns/prov#value Simultaneous overexpression of selenophosphate synthetase and phospholipid-hydroperoxide GSH peroxidase (PHGPx) [250] blocks activation of NF-kB by IL-1. Overexpression of SOD [84] or GSH peroxidase [81, 211] abolished NF-kB activation by preventing degradation of IkB after stimulation with TNF-a. The precise mechanism(s) through which oxidants and reductants influence activation of NF-kB is presently unknown; however, there is evidence that antioxidant enzyme (AOE372), a redox-sensitive thioredoxin peroxidase, regulates IkB phosphorylation [246]. Phosphatases The phosphatases are an important component of most signal transduction pathways, because failure to reverse kinase actions can disrupt normal cellular functions. For example, transfection of human fibroblasts with constitutively active ras (hRasV12) inhibits cell growth and ultimately results in a senescentlike phenotype [441]. Similarly, constitutive ERK activation has an inhibitory effect on cell cycle progression [442,443]. Both the serine/threonine phosphatases and the PTPs are known to be redox-sensitive [82,144,153,156,271,281, 444-449]. The mechanism of redox effects on activity is probably best understood for the PTPs. Without exception, the PTPs contain a highly conserved region of 11 amino acid residues in their catalytic domain; specifi- cally, (Ile/Val)-His-Cys-X-Ala-Gly-X-X-Arg-(Ser/Thr)- Gly, where X is a nonconserved amino acid [17]. Either oxidation or mutation of the cysteine renders these molecules inactive [17,281]. H2O2 is a potent inhibitor of PTPs. As in the case of other oxidants, H2O2 probably oxidizes the thiolate anion at the catalytic site [280]. Because formation of a phosphorylcysteine intermediate seems to be critical to PTP activity [450-452], blocking it through oxidation of the cysteine inactivates the molecules. In many cases, treatment of cells with H2O2 stimulates increases in protein phosphorylation by inhibiting phosphatase-catalyzed removal of phosphate groups. Furthermore, mitogens that increase cellular ox- idant production may stimulate phosphorylation indirectly by decreasing phosphatase activity. Additional mechanisms are involved in stimulation of pathways activated by growth factors that increase oxidant production, however, because there are known instances in which the oxidants they produce have no effect on protein phosphorylation. For example, TGF-b1 stimulates phosphorylation of numerous proteins and has been shown to cause a large increase in H2O2 production; however, its effects on protein phosphorylation are not blocked by catalase [453]. Furthermore, H2O2 is effective in promoting phosphorylation of phospholipase D, the PDGF receptor, and PKC-a even after pretreatment of Swiss 3T3 fibroblasts with orthovanadate to inhibit phosphatases [454]. Thus, although diminished phosphatase activity may partially account for increased phosphorylation in some cases, it cannot totally account for oxidation effects on phosphorylation in every case. SPECIFICITY In general, there is good agreement between studies on redox effects on any given gene; albeit, not all oxidizing or reducing treatments exert equivalent effects. This is clearly demonstrated in studies of pag , which encodes a protein associated with cellular proliferation. Pag protein inhibits the tyrosine kinase activity of the Abelson (abl ) protein by binding to its SH3-binding domain [455]. BSO, menadione, sodium arsenate, and diethyl maleate all stimulate pag expression, but H2O2 does not [269]. Conversely, H2O2 stimulates c-fos expression (Table 1), although 4-hydroynonenal (a product of v-6-polyunsaturated fatty acid peroxidation) not only fails to induce c-fos expression but is actually inhibitory to c-fos induction by EGF and PDGF [185]. Similarly, some oxidants such as diamide decrease hypoxia-induced signals [201], although others such as H2O2 increase them [124]. 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