Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) is an important inflammatory mediator and plays a central role in the destruction of connective tissue matrices in diseases such as arthritis and periodontitis. It is well established that IL-1 activation of the mitogen-activated protein (MAP) kinase pathway and induction of c-fos expression is a required step in the induction of matrix metalloproteinase expression involved in tissue degradation. Previous studies in our laboratory showed that IL-1-induced calcium flux is dependent on focal adhesion formation, suggesting a matrix-dependent restriction system for IL-1 signaling. Therefore, in the present study, we examined the consequences of this restriction on IL-1-mediated activation of the MAP kinase family and on c-fos expression. Treatment of human gingival fibroblasts with IL-1 activated extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase activity and induced c-fos expression in a dose- and time-dependent fashion. Plating cells on poly-L-lysine prevented focal adhesion formation, eliminated IL-1-induced calcium influx, abolished ERK stimulation, and blocked c-fos expression. Cells in suspension and hence with no suitable substratum for focal adhesion formation also showed no ERK activation or enhanced c-fos expression in response to IL-1. In contrast, eliminating focal adhesion formation or calcium depletion in cells plated on fibronectin had no effect on IL-1 stimulation of JNK and p38 kinases, demonstrating that their activation was mediated through pathways independent of focal adhesions and calcium. Calcium depletion abolished IL-1-induced calcium uptake, ERK activation, and c-fos expression. The focal adhesion dependence of IL-1-induced ERK activation and c-fos expression could be circumvented in cells plated on poly-L-lysine by simultaneous incubation with IL-1 and the calcium ionophore ionomycin. In transfection studies, IL-1 stimulation of serum responsive element (SRE) transcriptional activity was dependent on the presence of extracellular calcium. This is consistent with a requirement for calcium in the activation of ERKs and their involvement in the induction of c-fos expression through the SRE site on the 5' promoter of the c-fos gene. Our results demonstrate that in cells attached to substrates by focal adhesions, IL-1-mediated calcium flux is required for ERK activation and c-fos expression but not for JNK or p38 activation. We conclude that cellular interactions with the extracellular matrix play an important role in restricting ERK and c-fos-dependent processes.
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PMID:Requirements of focal adhesions and calcium fluxes for interleukin-1-induced ERK kinase activation and c-fos expression in fibroblasts. 950 15

Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. The signaling pathways through which retinoids mediate this effect have not been defined. Normal HBE cell growth is stimulated by treatment with a variety of growth factors that increase mitogen-activated protein (MAP) activity. In this study, we examined MAP kinase-dependent pathways as potential targets of retinoid signaling and the role of MAP kinases in retinoid-induced c-fos gene regulation. All-trans-retinoic acid (t-RA) inhibited Jun N-terminal kinase (JNK) and, to a lesser extent, extracellular signal-regulated kinase activity in normal HBE cells. t-RA reduced c-fos mRNA and protein levels by decreasing c-fos gene transcription. The c-fos promoter was activated by co-transfection with a constitutively active JNK kinase (SEK)-1 and suppressed by a dominant negative JNK kinase kinase (MEKK)-1. Furthermore, c-fos expression was inhibited by agonists of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), and suppression of c-fos promoter activity by t-RA was abrogated by treatment with antagonists of RAR-alpha or of all the RXRs. These findings provide the first evidence that t-RA inhibits JNK activity and demonstrate a potential role of JNK-dependent pathways in the suppression of c-fos expression by t-RA. Furthermore, c-fos expression was inhibited through activation of RAR- and RXR-dependent signaling pathways. In light of the growth activation induced by JNK/SEK-dependent pathways in a variety of cells, these data support further investigation into the role of JNK-dependent signaling in the growth-suppressive effects of retinoids.
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PMID:All-trans-retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways. 950 16

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14

Anisomycin, a translational inhibitor secreted by Streptomyces spp., strongly activates the stress-activated mitogen-activated protein (MAP) kinases JNK/SAPK (c-Jun NH2-terminal kinase/stress-activated protein kinase) and p38/RK in mammalian cells, resulting in rapid induction of immediate-early (IE) genes in the nucleus. Here, we have characterized this response further with respect to homologous and heterologous desensitization of IE gene induction and stress kinase activation. We show that anisomycin acts exactly like a signalling agonist in eliciting highly specific and virtually complete homologous desensitization. Anisomycin desensitization of a panel of IE genes (c-fos, fosB, c-jun, junB, and junD), using epidermal growth factor (EGF), basic fibroblast growth factor, (bFGF), tumor necrosis factor alpha (TNF-alpha), anisomycin, tetradecanoyl phorbol acetate (TPA), and UV radiation as secondary stimuli, was found to be extremely specific both with respect to the secondary stimuli and at the level of individual genes. Further, we show that anisomycin-induced homologous desensitization is caused by the fact that anisomycin no longer activates the JNK/SAPK and p38/RK MAP kinase cascades in desensitized cells. In anisomycin-desensitized cells, activation of JNK/SAPKs by UV radiation and hyperosmolarity is almost completely lost, and that of the p38/RK cascade is reduced to about 50% of the normal response. However, all other stimuli produced normal or augmented activation of these two kinase cascades in anisomycin-desensitized cells. These data show that anisomycin behaves like a true signalling agonist and suggest that the anisomycin-desensitized signalling component(s) is not involved in JNK/SAPK or p38/RK activation by EGF, bFGF, TNF-alpha, or TPA but may play a significant role in UV- and hyperosmolarity-stimulated responses.
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PMID:Anisomycin selectively desensitizes signalling components involved in stress kinase activation and fos and jun induction. 952 56

Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through glycoprotein (gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
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PMID:Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes. 954 5

Increasing evidence has suggested that locally produced angiotensin II (Ang II) plays an important role in the development of cardiac hypertrophy through the Ang II type 1 receptor (AT1). We and others have recently reported that Ang II is critical for mechanical stress-induced hypertrophic responses in vitro. Using AT1a knockout (KO) mice, we examined whether Ang II is indispensable for pressure overload-induced cardiac hypertrophy in the present study. Reverse-transcriptase polymerase chain reaction analysis revealed that AT1 mRNA levels were <10% in the heart of KO mice compared with wild-type (WT) mice, but the Ang II type 2 receptor gene was expressed at almost the same levels in the hearts of both mice. Intravenous infusion of subpressor dose of Ang II induced c-fos gene expression in the hearts of WT mice but not KO mice. Acute pressure overload, however, induced expressions of immediate-early response genes and activations of mitogen-activated protein kinases in the hearts of KO mice as well as WT mice. Both basal and activated levels of all these responses were significantly higher in KO mice than in WT mice. Pressure overload markedly increased the heart weight-to-body weight ratio in both mice strains at 14 days after aortic banding. These results suggest that acute hypertrophic responses could be induced by pressure overload in the in vivo heart without AT1 signaling.
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PMID:Acute pressure overload could induce hypertrophic responses in the heart of angiotensin II type 1a knockout mice. 956 37

Recent evidence indicates that the epidermal growth factor (EGF) receptor mediates a branch of lysophosphatidic acid (LPA)-induced signal transduction pathways that activate mitogen-activated protein (MAP) kinase. However, it is unclear whether the intrinsic tyrosine kinase activity of EGF receptor is involved. We previously showed that reactive oxygen species (ROS) were involved in the LPA-stimulated MAP kinase pathway. Here, we identify tyrosine phosphorylation of EGF receptor as an LPA signaling step that requires ROS. To evaluate the role of the tyrosine kinase activity of EGF receptor in the LPA-stimulated MAP kinase pathway, we examined the effects of an EGF receptor-specific tyrosine kinase inhibitor, PD158780. PD158780 potently inhibited the LPA-stimulated MAP kinase kinase 1/2 (MKK1/2) activation and EGF receptor tyrosine phosphorylation in HeLa cells, while it had no detectable effect on c-Src kinase activity. PD158780 also inhibited LPA-induced MKK1/2 activation and DNA synthesis in NIH 3T3 cells. Furthermore, we compared LPA-stimulated MKK1/2 and MAP kinase activation, transcriptional activity of the c-fos promoter, and DNA synthesis in B82L cells, which lack endogenous EGF receptor, and B82L cells expressing kinase-defective or wild-type human EGF receptor. Results obtained from analysis of these cell lines suggest that the EGF receptor tyrosine kinase contributes to the LPA-stimulated MAP kinase activation, c-fos transcription, and mitogenesis.
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PMID:Role of tyrosine kinase activity of epidermal growth factor receptor in the lysophosphatidic acid-stimulated mitogen-activated protein kinase pathway. 960 60

We showed before that in neonatal rat cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophic growth and transcriptional regulations of genes that are markers of cardiac hypertrophy. In view of the suggested roles of Ras and p42/44 mitogen-activated protein kinases (MAPKs) as key mediators of cardiac hypertrophy, the aim of this work was to explore their roles in ouabain-initiated signal pathways regulating four growth-related genes of these myocytes, i.e. those for c-Fos, skeletal alpha-actin, atrial natriuretic factor, and the alpha3-subunit of Na+/K+-ATPase. Ouabain caused rapid activations of Ras and p42/44 MAPKs; the latter was sustained longer than 90 min. Using high efficiency adenoviral-mediated expression of a dominant-negative Ras mutant, and a specific inhibitor of MAPK kinase (MEK), activation of Ras-Raf-MEK-p42/44 MAPK cascade by ouabain was shown. The effects of the mutant Ras, an inhibitor of Ras farnesylation, and the MEK inhibitor on ouabain-induced changes in mRNAs of the four genes indicated that (a) skeletal alpha-actin induction was dependent on Ras but not on p42/44 MAPKs, (b) alpha3 repression was dependent on the Ras-p42/44 MAPK cascade, and (c) induction of c-fos or atrial natriuretic factor gene occurred partly through the Ras-p42/44 MAPK cascade, and partly through pathways independent of Ras and p42/44 MAPKs. All ouabain effects required extracellular Ca2+, and were attenuated by a Ca2+/calmodulin antagonist or a protein kinase C inhibitor. The findings show that (a) signal pathways linked to sarcolemmal Na+/K+-ATPase share early segments involving Ca2+ and protein kinase C, but diverge into multiple branches only some of which involve Ras, or p42/44 MAPKs, or both; and (b) there are significant differences between this network and the related gene regulatory pathways activated by other hypertrophic stimuli, including those whose responses involve increases in intracellular free Ca2+ through different mechanisms.
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PMID:Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. 961 40

3-methylcholanthrene (MC), a potent promutagen and procarcinogen, is also an inducer of mammalian CYPIAI (cytochrome P1-450) gene. The CYPIAI enzyme is responsible for the detoxification of MC and its oxidation into reactive epoxide intermediates. Through its epoxide metabolites, MC functions also as an inducer of drug-metabolizing enzyme glutathione S-transferase (GST) gene expression. Induction of murine GST Ya gene by MC and a variety of other chemical agents is mediated by a regulatory element composed of two adjacent AP-1-like sites, and activated by the Fos/Jun heterodimeric complex (AP-1). In cultured cells, MC causes the induction of AP-1 activity, which is the result of an increased expression of c-Fos and c-Jun proteins. The mechanisms involved in MC activation of c-fos and c-jun gene expression were examined in the present study. Evidence is presented that stimulation of c-fos transcription by MC involves a signal transduction pathway, which includes activation of the small G protein Ras, Raf-1 kinase, and the mitogen-activated protein (MAP) kinases, ERK1 and ERK2. Furthermore, we find that phorbol 12-myristate 13-acetate, which uses both protein kinase C and protein-tyrosine kinase activities to induce c-fos promoter, may share a common pathway with MC downstream of Ras. The signal transduction pathway induced by MC to stimulate c-jun promoter involves Ras activation and the JNK group of MAP-kinases.
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PMID:Signaling pathways in the induction of c-fos and c-jun proto-oncogenes by 3-methylcholanthrene. 963 28

Certain nutrients and growth factors can stimulate pancreatic beta-cell growth. However, the appropriate mitogenic signaling pathways in beta-cells have been relatively undefined. In this study, differential gene expression in NEDH rat insulinoma was compared with NEDH rat primary islet beta-cells. Differential mRNA display analysis revealed an elevated expression in insulinoma of VL30 transposons, S24 ribosomal protein, and cytochrome-C oxidaseVIIc that is typical for cells undergoing mitosis. A gene candidate approach revealed that mRNA levels of the oncogenes c-fos and c-jun were equivalently expressed in insulinoma and islet cells, as was the mRNA for the mitogenic signal transduction molecule insulin receptor substrate (IRS)-1. However, in contrast to that of IRS-1, IRS-2 gene expression was 60- to 70-fold higher in the insulinoma tissue compared with islets, which was reflected at the protein as well as the mRNA level. The specific elevated IRS-2 expression was a consistent observation across all rodent pancreatic beta-cell lines. To investigate whether IRS-2 was functional, serum-stimulated beta-cell proliferation was examined in isolated insulinoma cells. After a 48-h period of serum withdrawal, 24 h of serum refeeding rendered an 8- to 10-fold increase in [3H]thymidine incorporation into insulinoma cells. This serum-stimulated DNA synthesis was prevented by inhibitors of tyrosine protein kinase and phosphatidylinositol (PI) 3-kinase activities, as well as the activation of mitogen-activated protein (MAP) kinase and p70S6K. Examination of IRS-mediated signal transduction pathways indicated that after 10-15 min of serum refeeding, there was increased tyrosine phosphorylation of IRS-2 and pp60, and PI 3-kinase recruitment to IRS-2. Serum also increased the association of growth factor-bound protein 2/murine sons of sevenless 1 protein to a PI 3-kinase/IRS-2 protein complex. Moreover, serum also activated MAP-kinase (erk-1 and erk-2 isoforms) and 70 kD S6 kinase. Thus IRS-mediated signal transduction pathways are functional in pancreatic beta-cells. It is conceivable that IRS-2 expression in beta-cells contributes to maintaining the islet beta-cell population, complementary to observations in the IRS-2 knockout mouse in which beta-cell mass is markedly reduced.
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PMID:A specific increased expression of insulin receptor substrate 2 in pancreatic beta-cell lines is involved in mediating serum-stimulated beta-cell growth. 964 31


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