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)

Thapsigargin is a non-phorbol ester-type tumor promoter that elevates the intracellular Ca2+ (Ca(i)2+) levels by blocking the microsomal Ca2+ ATPase. At present, the consequence of this Ca(i)2+ increase and the nature of the tumorigenicity of thapsigargin still remain to be elucidated. Previously, we demonstrated that thapsigargin activates the mitogen-activated protein (MAP) kinase via Ca(i)2+ but independently of protein kinase C or Ca2+ influx. Here, we show that thapsigargin also rapidly stimulates the Src tyrosine kinase. Transfection of a v-Src gene into a hippocampal cell line (H19-7) renders a constitutive activation of MAP kinase, whereas transfection of a kinase-deficient Src mutant blocks the activation by thapsigargin, suggesting that Src is required for the thapsigargin-induced MAP kinase activation. Cotransfection of a dominant-inhibitory Raf-1 and the v-Src genes into H19-7 cells results in an inhibition of the otherwise constitutively elevated MAP kinase activity, suggesting that Raf-1 is required for the Src-dependent activation of MAP kinase. Similarly, in the LA-90 cells, expression of a temperature-sensitive allele of v-Src constitutively activates Raf-1 and MAP kinase, whereas expression of a dominant-inhibitory Raf-1 mutant abolishes the MAP kinase activation induced by either v-Src or thapsigargin treatment. Together, these results suggest that thapsigargin stimulates MAP kinase signaling via Src and Raf-1. The activation of this Src-MAP kinase pathway suggests a biochemical mechanism for the tumorigenic nature of thapsigargin.
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PMID:Src tyrosine kinase mediates stimulation of Raf-1 and mitogen-activated protein kinase by the tumor promoter thapsigargin. 924 45

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

We previously demonstrated that the marine toxin and skin tumor promoter palytoxin activates the stress-activated protein kinase/c-Jun N-terminal kinase (JNK), but not the extracellular signal-regulated kinase (ERK), which is typically activated by mitogenic agents. JNK, ERK, and p38, another stress-activated protein kinase, are members of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases, which coordinate the transmission of various signals through the cell. The Na+,K+-ATPase is the putative palytoxin receptor. Therefore, we hypothesized that the Na+,K+-ATPase inhibitor ouabain might also stimulate signaling pathways that activate MAP kinases. Using HeLa and COS7 cells, we found that, although there are similarities between the protein kinase cascades by which palytoxin and ouabain activate JNK, there are also significant differences between the activation of specific MAP kinases by palytoxin and ouabain. Transient expression of dominant negative mutants indicates that ouabain, like palytoxin, activates JNK through a protein kinase cascade that involves the JNK kinase SEK1 but does not require the GTPase Ras. Palytoxin activates JNK and p38 to a greater extent than ouabain. By contrast, ouabain activates ERK to a greater extent than palytoxin. Ouabain blocked palytoxin-stimulated activation of JNK and p38, but not anisomycin-stimulated activation of these kinases, supporting the conclusion that ouabain and palytoxin bind to the same site on the Na+,K+-ATPase. These results suggest that the Na+,K+-ATPase can differentially mediate the activation of MAP kinases by two diverse ligands, palytoxin and ouabain.
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PMID:Differential activation of mitogen-activated protein kinases by palytoxin and ouabain, two ligands for the Na+,K+-ATPase. 970 14

We have previously shown that the mutation of the Schizosaccharomyces pombe PPZ-like protein phosphatase encoded by the gene pzh1+ results in increased tolerance to sodium and in hypersensitivity to potassium ions. A similar phenotype has also been reported for deletants in the spm1/pmk1 gene, encoding a mitogen-activated protein (MAP) kinase. We have found that the sodium tolerance phenotype of pzh1 deletants is stronger than that of spm1 mutants, and both effects are additive. Therefore, most probably both gene products mediate different pathways on sodium tolerance. In our hands, mutation of the kinase does not alter the tolerance to potassium, but it yields cells more tolerant to magnesium ions. While in budding yeast the mutations are synthetically lethal, fission yeast cells lacking both the phosphatase and the kinase genes are viable. Interestingly, their ability to export H+ to the medium is greatly impaired (although not that of pzh1 or spm1 single mutants). We have observed that, although the amount of the H+-ATPase in the plasma membrane is not altered, the activity of the enzyme is lower than normal and cannot be induced by glucose. These observations suggest that the activity of the H+-ATPase in fission yeast might be regulated by phospho-dephosphorylation mechanisms that might involve the pzh1+ and spm1+ gene products.
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PMID:The Pzh1 protein phosphatase and the Spm1 protein kinase are involved in the regulation of the plasma membrane H+-ATPase in fission yeast. 976 18

We showed before that in cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca2+-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of ouabain: inductions of the genes of skeletal alpha-actin and atrial natriuretic factor, repression of the gene of the alpha3-subunit of Na+/K+-ATPase, activation of mitogen-activated protein kinases, activation of Ras-dependent protein synthesis, and activation of transcription factor NF-kappaB. Induction of c-fos and activation of AP-1 by ouabain were not sensitive to NAC. Ouabain-induced inhibition of active Rb+ uptake through Na+/K+-ATPase and the resulting rise in intracellular Ca2+ were also not prevented by NAC. A phorbol ester that also causes myocyte hypertrophy did not increase ROS generation, and its effects on marker genes and protein synthesis were not affected by NAC. We conclude the following: (a) ROS are essential second messengers within some but not all signal pathways that are activated by the effect of ouabain on Na+/K+-ATPase; (b) the ROS-dependent pathways are involved in ouabain-induced hypertrophy; (c) increased ROS generation is not a common response of the myocyte to all hypertrophic stimuli; and (d) it may be possible to dissociate the positive inotropic effect of ouabain from its growth-related effects by alteration of the redox state of the cardiac myocyte.
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PMID:Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. 1038 43

In Schizosaccharomyces pombe, the Wis1-Sty1 MAP (mitogen-activated protein) kinase signaling cascade is known to play a major role in cellular adaptation to adverse external stimuli, including osmotic stress, oxidative stress, nutrient deprivation, DNA-damaging agents, and heat stress. Nonetheless, it is not known whether or not this particular MAPK cascade is also involved in response to the most common stress, salinity. In this study, we provide evidence that the Wis1-Sty1 MAP cascade is implicated in salt stress response through regulating expression of a salinity-inducible gene. The downstream target gene thus identified is the cta3+ gene, which encodes a cation-transporting P-type ATPase. The salt stress-responsive nature of cta3+ expression was characterized extensively. It was found that not only the Sty1 MAP kinase but also the Atf1 transcription factor is crucial for the inducible expression of cta3+. As far as we know, this is the first instance that the stress-activated Wis1-Sty1 MAPK cascade plays a role in salt stress response in S. pombe.
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PMID:The cta3+ gene that encodes a cation-transporting P-type ATPase is induced by salt stress under control of the Wis1-Sty1 MAPKK-MAPK cascade in fission yeast. 1042 98

Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.
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PMID:Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. 1051 68

Doxorubicin (DOX)-induced cardiomyopathy has been found to be associated with impaired Ca(2+) handling in the sarcoplasmic reticulum (SR), leading to reduced cardiac function. We have recently demonstrated that expression of mRNA encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 (SERCA2), a major Ca(2+) transport protein in SR, is markedly decreased in DOX-treated hearts. To extend this observation, we have dissected the molecular mechanisms by which DOX downregulates SERCA2 gene transcription. Using cultured rat neonatal cardiac myocytes, we found that the antioxidant N-acetylcysteine blocked the DOX-induced decrease in SERCA2 mRNA levels, as well as the DOX-induced increase in H(2)O(2) concentration; thus, H(2)O(2) is an intracellular mediator of DOX activity. Using a luciferase reporter assay, we found that the sequence from -284 to -72 bp in the 5' flanking region of the SERCA2 gene has a DOX-responsive element. Although several transcription factors have putative binding motifs in this region of the SERCA2 gene, only the expression of Egr-1 mRNA and the binding of Egr-1 protein to the 5' regulatory sequence of SERCA2 gene increased markedly after DOX administration. We also found that overexpression of Egr-1 was associated with a significant reduction in SERCA2 gene transcription. In addition, Egr-1 antisense oligonucleotides blocked the DOX-induced reduction in SERCA2 mRNA, suggesting that Egr-1 is a transcriptional inhibitor of the SERCA2 gene in DOX-induced cardiomyopathy. We observed activation of 3 mitogen-activated protein kinases (MAPKs), p44/42 MAPK, p38 MAPK, and stress-activated MAPK/Jun N-terminal kinase, by DOX, but only a specific inhibitor of the p44/42 MAPK kinase suppressed the effects of DOX on Egr-1 and SERCA2 mRNA expression. These findings indicate that reactive oxygen intermediates, the transcription factor Egr-1, and p44/42 MAPK are critical elements in the transcriptional regulation of the SERCA2 gene in response to DOX.
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PMID:Mechanism of doxorubicin-induced inhibition of sarcoplasmic reticulum Ca(2+)-ATPase gene transcription. 1062 99

p38 is a member of the mitogen-activated protein (MAP) kinase family. Activation (phosphorylation) of p38 acts as a switch for the transcriptional and translational regulation of a number of proteins, including the proinflammatory cytokines. Investigation of a set of small peptides revealed that, as with protein substrates, p38-alpha behaves as a proline-directed Ser/Thr MAP kinase for a peptide substrate, peptide 4 (IPTSPITTTYFFFKKK). We investigated the steady-state kinetic mechanism of the p38-alpha-catalyzed kinase reaction with EGF receptor peptide, peptide 1, as a substrate. Lineweaver-Burk analysis of the substrate kinetics yielded a family of lines intersecting to the left of the ordinate, with either ATP or peptide 1 as the varied substrate. Kinetic analysis in the presence of ADP yielded a competitive inhibition pattern when ATP was the varied substrate and a noncompetitive pattern if peptide 1 was the varied substrate. At saturating peptide substrate concentrations, inhibition by phosphopeptide product yielded an uncompetitive pattern when ATP was the varied substrate. These data are consistent with ordered binding with ATP as the initial substrate. We provide further evidence of the existence of a productive p38.ATP binary complex in that (a) activated p38-alpha has intrinsic ATPase activity, (b) ATPase and kinase activities are coupled, and (c) inhibitors of ATPase activity also inhibit the kinase activity with a similar inhibition constant. The k(cat) for the kinase reaction was lowered by 1.8-fold when ATP-gamma-S was used. Microviscosity linearly affected the k(cat) values of both the ATP and ATP-gamma-S reactions with a slope of about 0.8. These observations were interpreted to mean that the phosphoryl transfer step is not rate-limiting and that the release of product and/or enzyme isomerization is a possible rate-limiting step(s).
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PMID:Kinetic mechanism of the p38-alpha MAP kinase: phosphoryl transfer to synthetic peptides. 1068 58

Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
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PMID:ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. 1071 38


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