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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAccZm_srTbANBvsXG_7dQ5ZvfDmRj3Gh-eWGzpzCq-g4#_5 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAccZm_srTbANBvsXG_7dQ5ZvfDmRj3Gh-eWGzpzCq-g4#_4 http://www.w3.org/ns/prov#value Activation of all MAP kinases depends on dual phosphorylation of specific tyrosine and threonine residues, which are located on the TXY motif in the linker loop 12 (L12) region of the kinase subdomain VIII [373]. These reactions are catalyzed by dual-specificity threonine and tyrosine kinases belonging to the MKK family (Fig. 1). Specificity is determined by the sequence of the TXY motif as well as by the length of the L12 loop. A relatively large number of intracellular proteins with diverse functions and different subcellular localization [374-378] have been identified as targets for phosphorylation by the MAP kinases. Members of the ERK, JNK (Fig. 1), and p38 MAP kinase subfamilies phosphorylate the COOH-terminal transcriptional activation domain of Elk-1 and SAP-1 [379-385], which then associates with other nuclear proteins to form TCF. The TCF proteins belong to a subgroup of the Etsdomain family of transcription factors, which includes Elk-1, SAP-1 [386,387], and NET-1/ERP/SAP-2 [388]. TCF proteins are incapable of autonomous binding to the promoter region and thus require interaction with other transcription factors such as the SRF [389,390]. Transcriptional activation of many genes is mediated by binding a multiprotein complex comprising an SRF homodimer and a member of the TCF family [391,392] to the SRE in their promoter region. The SRE cis-acting element (Fig. 1) was initially identified as the region in the promoter of c-fos and other immediate-early response genes responsible for their transcriptional induction on serum stimulation [393,394]. SRE also mediates increased gene expression in cells treated with specific growth factors, phorbol esters, and cytokines or subjected to environmental stress [381]. Two other critical promoter regions are the sis-inducible element and the CRE. Binding to both of these elements is dependent on the presence of an intact SRE [395-399]. Although exceptions are known, in general, growth factors, phorbol esters, and antioxidant compounds induce the activation of the ERK isoforms p44ERK/ERK1 and p42ERK/ERK2, and exposure of cells to UV and various forms of environmental stress activates the JNK, p38, and big MAP kinase subfamilies [54,132,371,377]. Not surprisingly, the effects of oxidants and reductants on many 'redox-sensitive' genes are mediated through effects on the MAP kinases. For example, mitogen and stress-activated protein kinase (MSK-1) is activated by oxidative stress; however, the effect is mediated by the p38 and ERK pathways [242]. Similarly, UV irradiation of mouse cells stimulates phosphorylation of p53 apparently via the JNK-1 pathway [267]. The c-fos gene is one of the best-studied early response genes; it is stimulated by a variety of oxidizing and reducing treatments [27, 53,54,381]. Because many of the pathways leading to the induction of c-fos are known, an analysis of its induction by reductants and oxidants has been useful in elucidating the mechanisms by which perturbation of redox state alters gene expression (Fig. 1). Choi and Moore [78] demonstrated that an isolated c-fos SRE site responds to treatment with the phenolic antioxidants butylated hydroxytoluene (BHT) and BHA. Because phosphorylation of p62tcf (Elk-1) [400,401] is mediated by MAP kinase [390] and is required for activation of the SRE, these observations also implicate MAP kinases in mediating the effects of reducing agents on c-fos transcription (Table 1). NF-kB The NF-k-B/Rel family of transcription factors is involved in the regulation of numerous genes, including acute phase proteins, cell surface receptors, and cytokines; they also regulate certain viral genes [402-405]. 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