Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serum response element (SRE) is a promoter element essential for transcriptional activation of immediate early genes, such as c-fos and early growth response-1, by mitogenic signals. Several transcription factors bind the SRE, including the serum response factor (SRF), the ternary complex factor, and the CCAAT/enhancer-binding protein beta (C/EBPbeta). The C/EBPbeta mRNA encodes three translation products of 38, 35, and 20 kDa. p35-C/EBPbeta activates transcription of the SRE in an SRF-dependent fashion, whereas p20-C/EBPbeta, which initiates at an internal in-frame methionine, lacks a transactivation domain and inhibits transcription. We show that SRF and C/EBPbeta interact in vivo through the DNA binding domain of SRF and the C terminus of C/EBPbeta common to p35/38 and p20. Therefore, like the ternary complex factor, C/EBPbeta may be recruited to the SRE not only by binding to the DNA, which is not a high affinity site, but also by protein-protein interactions with SRF. Strikingly, in both the mammalian two-hybrid assay and in vivo coimmunoprecipitations, the association of SRF and p35-C/EBPbeta but not p20-C/EBPbeta is dramatically stimulated by activated Ras. Furthermore, mutation of the threonine within a mitogen-activated protein kinase consensus motif in the C terminus of C/EBPbeta eliminates the response to Ras. These results suggest a new mechanism by which mitogenic signals may influence transcription activity of the SRE by selectively promoting protein-protein interactions between SRF and the transactivator p35-C/EBPbeta.
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PMID:Ras regulates the association of serum response factor and CCAAT/enhancer-binding protein beta. 1031 42

The paradigm for the response to hypoxia is erythropoietin gene expression; activation of hypoxia-inducible factor-1 (HIF-1) results in erythropoietin production. Previously, we found that oxygen deprivation induced tissue factor, especially in mononuclear phagocytes, by an early growth response (Egr-1)-dependent pathway without involvement of HIF-1 (Yan, S.-F., Zou, Y.-S., Gao, Y., Zhai, C., Mackman, N., Lee, S., Milbrandt, J., Pinsky, D., Kisiel, W., and Stern, D. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8298-8303). Now, we show that cultured monocytes subjected to hypoxia (pO2 approximately 12 torr) displayed increased Egr-1 expression because of de novo biosynthesis, with a approximately 10-fold increased rate of transcription. Transfection of monocytes with Egr-1 promoter-luciferase constructs localized elements responsible for hypoxia-enhanced expression to -424/-65, a region including EBS (ets binding site)-SRE (serum response element)-EBS and SRE-EBS-SRE sites. Further studies with each of these regions ligated to the basal thymidine kinase promoter and luciferase demonstrated that EBS sites in the element spanning -424/-375 were critical for hypoxia-enhanceable gene expression. These data suggested that an activated ets factor, such as Elk-1, in complex with serum response factor, was the likely proximal trigger of Egr-1 transcription. Indeed, hypoxia induced activation of Elk-1, and suppression of Elk-1 blocked up-regulation of Egr-1 transcription. The signaling cascade preceding Elk-1 activation in response to oxygen deprivation was traced to activation of protein kinase C-betaII, Raf, mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase and mitogen-activated protein kinases. Comparable hypoxia-mediated Egr-1 induction and activation were observed in cultured hepatoma-derived cells deficient in HIF-1beta and wild-type hepatoma cells, indicating that the HIF-1 and Egr-1 pathways are initiated independently in response to oxygen deprivation. We propose that activation of Egr-1 in response to hypoxia induces a different facet of the adaptive response than HIF-1, one component of which causes expression of tissue factor, resulting in fibrin deposition.
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PMID:Hypoxia-associated induction of early growth response-1 gene expression. 1032 6

The small Ras-related GTPase, TC10, has been classified on the basis of sequence homology to be a member of the Rho family. This family, which includes the Rho, Rac and CDC42 subfamilies, has been shown to regulate a variety of apparently diverse cellular processes such as actin cytoskeletal organization, mitogen-activated protein kinase (MAPK) cascades, cell cycle progression and transformation. In order to begin a study of TC10 biological function, we expressed wild type and various mutant forms of this protein in mammalian cells and investigated both the intracellular localization of the expressed proteins and their abilities to stimulate known Rho family-associated processes. Wild type TC10 was located predominantly in the cell membrane (apparently in the same regions as actin filaments), GTPase defective (75L) and GTP-binding defective (31N) mutants were located predominantly in cytoplasmic perinuclear regions, and a deletion mutant lacking the carboxyl terminal residues required for post-translational prenylation was located predominantly in the nucleus. The GTPase defective (constitutively active) TC10 mutant: (1) stimulated the formation of long filopodia; (2) activated c-Jun amino terminal kinase (JNK); (3) activated serum response factor (SRF)-dependent transcription; (4) activated NF-kappaB-dependent transcription; and (5) synergized with an activated Raf-kinase (Raf-CAAX) to transform NIH3T3 cells. In addition, wild type TC10 function is required for full H-Ras transforming potential. We demonstrate that an intact effector domain and carboxyl terminal prenylation signal are required for proper TC10 function and that TC10 signals to at least two separable downstream target pathways. In addition, TC10 interacted with the actin-binding and filament-forming protein, profilin, in both a two-hybrid cDNA library screen, and an in vitro binding assay. Taken together, these data support a classification of TC10 as a member of the Rho family, and in particular, suggest that TC10 functions to regulate cellular signaling to the actin cytoskeleton and processes associated with cell growth.
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PMID:Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth. 1044 46

A search for transforming genes expressed in brain led to the identification of a novel isoform of Ost, an exchange factor for RhoA and Cdc42. In addition to the Dbl-homology (DH) and pleckstrin-homology (PH) domains identified in the original Ost, this isoform contained a SH3 domain and a novel HIV-Tat related (TR) domain. The presence or absence of these domains in Ost defined multiple isoforms of the protein. RT - PCR and in situ hybridization analysis revealed that these isoforms were generated by tissue-specific and developmentally restricted alternative splicing events. Whereas deletion of the N-terminus activated the transforming properties of Ost, the presence of the SH3 domain reduced the transforming activity of the protein. This inhibition was relieved by the presence of a TR domain, which contained a potential SH3 ligand sequence. The transforming activity of all Ost isoforms was inhibited by dominant negative forms of the Rho family proteins. Expression of Ost isoforms potently induced the formation of actin stress fibers and filopodia as well as JNK activity and AP1- and SRF-regulated transcriptional pathways. Ost transfectants also displayed elevated levels of cyclins A and D1, suggesting that the de-regulation of these cyclins is linked to Ost-mediated transformation.
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PMID:Distinct expression patterns and transforming properties of multiple isoforms of Ost, an exchange factor for RhoA and Cdc42. 1046 22

The ternary complex factor (TCF) subfamily of ETS-transcription factors represent key nuclear targets of the MAP kinase pathways. Members of this subfamily are classified by the presence of several conserved domains for DNA binding, interaction with SRF, interaction with MAP kinases and transcriptional activation. In this study we have isolated a further member of this subfamily (TCF-1) from zebrafish. The protein product of zebrafish TCF-1 (zTCF-1), shares sequence similarity with the mammalian TCFs in all four conserved domains, with highest overall similarity to SAP-1. Zebrafish TCF-1 is expressed throughout zebrafish embryonic development and exhibits typical TCF DNA binding characteristics, with the B-box being required for interaction with SRF. Of the mammalian TCFs, its DNA binding specificity resembles Elk-1. zTCF-1 is a target for both the growth factor/mitogen-activated and stress-activated MAP kinase cascades in vitro and in vivo. However, differential targeting occurs, with the profile of its activation closely resembling that of mammalian SAP-1. Together, our results demonstrate that the TCFs have been functionally conserved during vertebrate development.
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PMID:Molecular characterization of a zebrafish TCF ETS-domain transcription factor. 1063 9

Homocysteine (Hcy) exerts either promoting or suppressive effects on mitogenesis in a cell type-specific manner. Hcy elicits proliferation of vascular smooth muscle cells, but is rather inhibitory to growth of endothelial cells and NIH/3T3 cells. In NIH/3T3 cells, we found that physiologically relevant concentrations (20-100 microM) of Hcy inhibit the activity of activating protein-1 (AP-1) transcription factor, although it is capable of eliciting immediate-early signaling events. Hcy induced p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in control cells, but not in dominant negative p21ras transfected cells, indicating induction of the Ras-MAPK pathway. Hcy also induced the activity of serum response factor and expression of c-fos and c-jun genes. Despite the activation of these upstream events, Hcy potently inhibited AP-1 activity. Oxidized forms of Hcy (Hcy thiolactone, homocystine) were less effective in affecting AP-1. Hcy-mediated inhibition of AP-1 activity was not observed in A7r5 vascular smooth muscle cells. These results demonstrate that Hcy exerts cell type- and redox-specific inhibition of AP-1 dependent biological events.
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PMID:Homocysteine exerts cell type-specific inhibition of AP-1 transcription factor. 1065 89

Induction of cfos expression is a definite end point of signal transduction by receptor tyrosine kinases via MAPK cascades. We have examined signal transduction to transcription factor cFos in isolated fibroblasts of a patient with an inherited syndrome of insulin resistance. MAPK phosphorylation and activity were unaltered, but inducibility of cfos transcription was strongly impaired by insulin and reduced by PDGF. Induction of the cfos promoter via MAPK is mediated by activation of the ternary complex. Abundance of SRF or Elk-1 was unaltered, but Elk-1 phosphorylation following stimulation was reduced. Transient transfections with reporter genes under control of the Elk-1 binding ets/sre cis element or expression plasmids coding for the regulatory domain of Elk-1 fused to heterologous DNA binding domains revealed a defect of Elk-1 activation in the patient cells. These data identify a novel postreceptor defect of insulin and growth factors involving activation of transcription.
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PMID:Characterization of a postreceptor signaling defect that impairs cfos expression in cultured fibroblasts of a patient with insulin resistance. 1067 46

Ribosomal subunit kinases (Rsk) have been implicated in the regulation of transcription by phosphorylating and thereby activating numerous transcription factors, such as c-Fos, cAMP responsive element binding protein (CREB), and nuclear receptors. Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk-2 gene was disrupted by homologous recombinant gene targeting. Rsk-2-deficient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild-type control mice. KO cells exhibit a major reduction in platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1-stimulated expression of the immediate-early gene c-Fos. This results primarily from a reduced transcriptional activation of the ternary complex factor Elk-1 and reduced activation of the serum response factor. The reduced Elk-1 activation in KO cells occurs despite normal activation of the mitogen-activated protein kinase pathway and normal PDGF- and IGF-1-stimulated Elk-1 phosphorylation. By contrast, PDGF- and IGF-1-stimulated phosphorylation and transcriptional activation of CREB is unaltered in KO cells. Thus Rsk-2 is required for growth factor-stimulated expression of c-Fos and transcriptional activation of Elk-1 and the serum response factor, but not for activation of CREB or the mitogen-activated protein kinase pathway in response to PDGF and IGF-1 stimulation.
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PMID:Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene. 1071 83

The c-fos enhancer can be activated by many signaling pathways through distinct elements of the enhancer. The enhancer contains at its core the serum response element (SRE) that binds serum response factor (SRF). On the 5' side of the SRE is a site for p62TCF which binds only when SRF is bound as well. p62TCF is encoded by three ets-related genes, Elk-1, SAP1 and SAP2. Each of these factors contain a transcriptional activation domain that is activated by phosphorylation by MAP kinases. On the 3' side of the SRE is the 'c-fos AP1 site' (FAP1) whose role has been less clear. We find here that the FAP1 site contributes strongly to phorbol ester (TPA) and Erk MAP kinase activation of the c-fos enhancer and that both the p62TCF and FAP1 sites are required for effective activation of the enhancer. We further find that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.
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PMID:Activation of the c-fos enhancer by the erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites. 1072 28

Exposure of vascular smooth muscle cells to arginine vasopressin (AVP) increases smooth muscle alpha-actin (SM-alpha-actin) expression through activation of the SM- alpha-actin promoter. The goal of this study was to determine the role of the mitogen-activated protein kinase (MAP kinase) family in regulation of SM-alpha-actin expression. AVP activated all three MAP kinase family members: ERKs, JNKs, and p38 MAP kinase. Inhibition of JNKs or p38 decreased AVP-stimulated SM-alpha-actin promoter activity, whereas inhibition of ERKs had no effect. A 150-base pair region of the promoter containing two CArG boxes was sufficient to mediate regulation by vasoconstrictors. Mutations in either CArG box decreased AVP-stimulated promoter activity. Electrophoretic mobility shift assays using oligonucleotides corresponding to either CArG box resulted in a complex of similar mobility whose intensity was increased by AVP. Antibodies against serum response factor (SRF) completely super-shifted this complex, indicating that SRF binds to both CArG boxes. Overexpression of SRF increased basal promoter activity, but activity was still stimulated by AVP. AVP stimulation rapidly increased SRF phosphorylation. These data indicate that both JNKs and p38 participate in regulation of SM- alpha-actin expression. SRF, which binds to two critical CArG boxes in the promoter, represents a potential target of these kinases.
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PMID:Induction of smooth muscle alpha-actin in vascular smooth muscle cells by arginine vasopressin is mediated by c-Jun amino-terminal kinases and p38 mitogen-activated protein kinase. 1080 20


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