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

PC12 cell differentiation was induced by one week of nerve growth factor (NGF) treatment and adenosine A2A receptor expression and activity were analysed. Undifferentiated PC12 cells expressed very high levels of adenosine A2A receptors (approximately equal to 2 pmol/mg) and exhibited strong cyclic AMP (cAMP) responses when stimulated with the selective adenosine A2A receptor agonist 2-[p-(2-carbonylethyl) phenylethylamino-5'-N-ethylcarboxamidoadenosine]. NGF-induced differentiation was accompanied by a down-regulation of adenosine A2A receptors: receptor binding decreased to 500 fmol/mg, immunoreactive A2A receptor protein was decreased by about half and cAMP production was reduced by 60%. In situ hybridization experiments demonstrated a heterogenous distribution of A2A receptor mRNA and a decreased number of strongly labelled cells after NGF treatment. Stimulation of the cells with the non-selective adenosine receptor agonist N-ethylcarboxamidoadenosine (NECA) inhibited NGF-induced mitogen-activated protein kinase activation. These results thus show that NGF-induced differentiation of PC12 cells is accompanied by a decrease in A2A receptor-mediated cAMP accumulation. This might be a way for PC12 cells to counteract an inhibitory effect of A2A receptor activation on some aspects of neurotrophin signalling.
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PMID:Down-regulation of adenosine A2A receptors upon NGF-induced differentiation of PC12 cells. 936 87

Phosphorylation of alphaB-crystallin, a member of the hsp27 family, in human glioma (U373 MG) cells was stimulated by exposure of the cells to various stimuli, which included heat, arsenite, phorbol 12-myristate 13-acetate (PMA), okadaic acid, H2O2, anisomycin, and high concentrations of NaCl or sorbitol, but not in response to agents that elevated intracellular levels of cyclic AMP. Cells exposed to PMA together with okadaic acid yielded three bands of 32P-labeled alphaB-crystallin when immunoprecipitated samples were subjected to electrophoresis on an isoelectric focusing gel. All of the phosphorylated residues were identified as serine, an indication that three different serine residues can act as sites of phosphorylation in alphaB-crystallin. Structural analysis by mass spectrometry revealed that phosphorylation of alphaB-crystallin occurred at serines 19, 45, and 59. Dithiothreitol and staurosporine selectively inhibited the phosphorylation induced by arsenite and the phorbol ester, respectively. SB202190, an inhibitor of p38 mitogen-activated protein (MAP) kinase, suppressed the phosphorylation induced by arsenite, anisomycin, H2O2, sorbitol, NaCl, and heat shock, but not that induced by PMA and okadaic acid. The PMA-induced phosphorylation was selectively suppressed by an inhibitor of p44 MAP kinase kinase, PD98059. Although PMA and arsenite preferentially stimulated the phosphorylation of Ser-45 and Ser-59, respectively, as determined with antibodies that recognized the respective phosphorylated forms of alphaB-crystallin, all three sites were phosphorylated in response to each stimulus. These results suggest that p38 MAP kinase or p44 MAP kinase might be involved in the signal transduction cascade that leads to the phosphorylation of alphaB-crystallin. The phosphorylation of alphaB-crystallin was also enhanced in the heart and diaphragm when rats were exposed to heat stress (42 degrees C for 20 min).
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PMID:Phosphorylation of alphaB-crystallin in response to various types of stress. 936 70

1. The blood-brain barrier is formed by capillary endothelial cells and is regulated by cell-surface receptors, such as the G protein-coupled P2Y receptors for nucleotides. Here we investigated some of the characteristics of control of brain endothelial cells by these receptors, characterizing the phospholipase C and Ca2+ response and investigating the possible involvement of mitogen-activated protein kinases (MAPK). 2. Using an unpassaged primary culture of rat brain capillary endothelial cells we showed that ATP, UTP and 2-methylthio ATP (2MeSATP) give similar and substantial increases in cytosolic Ca2+, with a rapid rise to peak followed by a slower decline towards basal or to a sustained plateau. Removal of extracellular Ca2+ had little effect on the peak Ca2+-response, but resulted in a more rapid decline to basal. There was no response to alpha,beta-MethylATP (alpha,beta MeATP) in these unpassaged cells, but a response to this P2X agonist was seen after a single passage. 3. ATP (log EC50 -5.1+/-0.2) also caused an increase in the total [3H]-inositol (poly)phosphates ([3H]-InsPx) in the presence of lithium with a rank order of agonist potency of ATP=UTP=UDP>ADP, with 2MeSATP and alpha,beta MeATP giving no detectable response. 4. Stimulating the cells with ATP or UTP gave a rapid rise in the level of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), with a peak at 10 s followed by a decline to a sustained plateau phase. 2MeSATP gave no detectable increase in the level of Ins(1,4,5)P3. 5. None of the nucleotides tested affected basal cyclic AMP, while ATP and ATPgammaS, but not 2MeSATP, stimulated cyclic AMP levels in the presence of 5 microM forskolin. 6. Both UTP and ATP stimulated tyrosine phosphorylation of p42 and p44 mitogen-activated protein kinase (MAPK), while 2MeSATP gave a smaller increase in this index of MAPK activation. By use of a peptide kinase assay, UTP gave a substantial increase in MAPK activity with a concentration-dependency consistent with activation at P2Y2 receptors. 2MeSATP gave a much smaller response with a lower potency than UTP. 7. These results are consistent with brain endothelial regulation by P2Y2 receptors coupled to phospholipase C, Ca2+ and MAPK; and by P2Y1-like (2MeSATP-sensitive) receptors which are linked to Ca2+ mobilization by a mechanism apparently independent of agonist stimulated Ins(1,4,5)P3 levels. A further response to ATP, acting at an undefined receptor, caused an increase in cyclic AMP levels in the presence of forskolin. The differential MAPK coupling of these receptors suggests that they exert fundamentally distinct influences over brain endothelial function.
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PMID:Regulation of brain capillary endothelial cells by P2Y receptors coupled to Ca2+, phospholipase C and mitogen-activated protein kinase. 938 12

Numerous studies with PC12 cells have suggested that the mitogen-activated protein (MAP) kinase pathway might play a major role in the neuronal differentiation that is induced by nerve growth factor (NGF). Cells of the PC12D subline extend neurites within several hours in response to NGF in the presence of inhibitors of the synthesis of RNA and protein. We examined the effects of a specific inhibitor 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059) of the MAP kinase kinase (MEK)/MAP kinase pathway on the NGF-induced outgrowth of neurites in PC12D cells. The increase in MAP kinase activity in response to NGF was reduced by 80% upon treatment of PC12D cells with 50 microM PD98059, whereas the NGF-dependent formation of ruffles and the subsequent outgrowth of neurites were not blocked by PD98059 at this concentration. The outgrowth of neurites from conventional PC12 cells by NGF was suppressed by the addition of 50 microM PD98059 as reported by Pang et al. [L. Pang, T. Sawada, J. Stuart,S.J. Decker, A.R. Saltiel, Inhibition of MAP kinase kinase blocks the differentiation of PC12 cells induced by nerve growth factor, J. Biol. Chem. 270 (1995) 13585-13588]. In contrast, the rapid regeneration of neurites from PC12 cells primed with NGF, was not altered in the presence of the same dose of the inhibitor of MEK. It appeared, therefore, that the activation of the MAP kinase pathway was not necessarily required for the NGF-dependent extension of neurites. When PC12D cells were transfected with the dominant inhibitory Ha-ras Asn-17 gene, the induction of the mutant Ras protein led the suppression of the rapid outgrowth of neurites in response to NGF but not to dibutyryl cyclic AMP (dbcAMP). The result implies a direct involvement of Ras protein in the NGF-induced signal transduction that lead to the formation of neurites in PC12D cells. We can conclude that the activation of MAP kinase and selective gene expression are required for the differentiation of conventional PC12 cells to sympathetic neuron-like cells and that activation of Ras protein and, subsequently, of a MAP kinase-independent pathway might be involved in the extension of neurites from PC12D cells or in the regeneration of neurites from primed PC12 cells in response to NGF.
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PMID:Activation of mitogen-activated protein kinases is not required for the extension of neurites from PC12D cells triggered by nerve growth factor. 951 60

The challenge of 3T3-F442A fibroblasts with growth hormone led to both a decrease in the mobility on SDS/PAGE and activation of the PDE4A cyclic AMP-specific phosphodiesterase isoform PDE4A5. Activation was mediated by a JAK-2-dependent pathway coupled to the activation of phosphatidylinositol 3-kinase and p70S6 kinase. Activation was not dependent on the ability of growth hormone to stimulate ERK2 or protein kinase C or any effect on transcription. Blockade of activation of murine PDE4A5 ablated the ability of growth hormone to decrease intracellular cAMP levels. Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes. It is suggested that activation of PDE4A5 by growth hormone serves as a brake on the differentiation processes.
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PMID:Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. 952 Apr 3

We studied early changes in gene expression during fibroblast contraction of stressed collagen matrices. The level of c-fos mRNA increased dramatically and peaked 50 to 60 min after matrix contraction was initiated. This response did not require serum and could not be accounted for simply by disruption of the actin cytoskeleton. Increased c-fos mRNA levels required Ca2+ influx but not the cyclic AMP or extracellular signal-regulated kinase (ERK 1/2) signaling pathways, both of which are activated when fibroblasts contract stressed collagen matrices. The levels of two other immediate-early genes, fosb and c-jun, also increased transiently after fibroblast contraction, whereas the levels of fra-1, fra-2, c-myc, and the transcription factor NF-kappaB remained the same, indicating that fibroblast contraction caused changes in a selective group of genes. The increase in c-fos mRNA during contraction of stressed collagen matrices may reflect a unique role for c-fos in mechanoregulated events at the end of wound repair.
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PMID:Increased c-fos mRNA expression by human fibroblasts contracting stressed collagen matrices. 956 85

Activation of cytochrome c (cyt c) transcription in electrically stimulated neonatal rat cardiac myocytes is preceded by transient expression of the activating protein-1 family of transcription factors, c-Fos, c-Jun, and JunB, as well as nuclear respiratory factor-1 (NRF-1). Mutations in either the NRF-1 or in the two cyclic AMP response elements on the cyt c promoter significantly reduce cyt c promoter activation produced either by electrical stimulation (Xia, Y., Buja, L. M., Scarpulla, R. C., and McMillin, J. B. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 11399-11404) or by transfection of c-jun into nonpaced cardiac myocytes. Electrical stimulation of cardiac myocytes activates the c-Jun N-terminal kinase (McDonough, P. M., Hanford, D. S., Sprenkle, A. B., Mellon, N. R., and Glembotski, C. C. (1997) J. Biol. Chem. 272, 24046-24053) so that the fold-activation of the cyt c promoter is increased by pacing when either c-jun or c-fos/c-jun were cotransfected. Physical association of NRF-1 protein with the NRF-1 enhancer element and of c-Jun with the cyclic AMP response element binding sites on the cyt c promoter was demonstrated by gel shift competition assays and by antibody super shifts. This is the first demonstration that induction of NRF-1 and c-Jun by pacing of cardiac myocytes directly mediates cyt c gene expression and mitochondrial proliferation in response to hypertrophic stimuli in the heart.
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PMID:Activation of the cytochrome c gene by electrical stimulation in neonatal rat cardiac myocytes. Role of NRF-1 and c-Jun. 957 20

1. Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD-1 cells. 2. In DLD-1 cells, interferon--gamma alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon-gamma, tumour necrosis factor-alpha and interleukin-1beta produced maximal NOS II induction. 3. Activators of protein kinase A (forskolin, 8-dibutyryl-cyclic AMP), of protein kinase C (tetradecanoylphorbol-13-acetate), and of protein kinase G (8-bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. 4. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3-kinase (wortmannin), of p38 mitogen-activated protein kinase (compound SB 203580) and of extracellular signal-regulated kinase (compound PD 98059) also had no influence on basal or cytokine-induced NOS II mRNA expression. 5. Immunoprecipitation kinase assays showed no activation of extracellular signal-regulated kinase or p38 mitogen-activated protein kinase in cytokine-incubated DLD-1 cells. The c-Jun NH2-terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor-alpha which did not induce NOS II by itself. 6. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon-gamma-activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM-induced NOS II mRNA expression in a concentration-dependent manner. 7. These results suggest that activation of NOS II expression in DLD-1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3-kinase, extracellular signal regulated kinase and p38 mitogen-activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon-gamma-activated janus kinase 2.
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PMID:Involvement of protein kinases in the induction of NO synthase II in human DLD-1 cells. 960 80

Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.
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PMID:Vascular dopamine-I receptors and atherosclerosis. 963 15

Neurotrophic factors prevent apoptosis of PC12 cells in serum-free medium. The present study determines whether neurotrophic factors can prevent ceramide-induced apoptosis in PC12 cells and investigates the role that c-Jun N-terminal kinase (JNK) activation may play in this system. Ceramide-induced apoptosis was inhibited by nerve growth factor, basic fibroblast growth factor, pituitary adenylyl cyclase-activating peptide, 4-(8-chlorophenylthio)cyclic AMP, and the caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp fluoromethyl ketone (zVAD-FMK). It was surprising that inhibition of extracellular signal-regulated kinase and/or phosphatidylinositol 3-kinase did not markedly block the protective effects exerted by neurotrophic factors against ceramide-induced apoptosis, suggesting that neurotrophic factors can promote survival independently of these signaling pathways. Treatment of PC12 cells with ceramide resulted in a time-dependent increase in JNK activity. However, neither neurotrophic factors nor zVAD-FMK attenuated ceramide-stimulated JNK activation. Further experiments indicated that ceramide-induced apoptosis in PC12 cells requires new protein synthesis, and that nerve growth factor and zVAD-FMK can prevent apoptosis after JNK activity has been detected. These results indicate that ceramide-induced JNK activation is an early event and may be required for the expression of essential components of the apoptotic machinery. It is anticipated that neurotrophic factors inhibit ceramide-induced apoptosis by affecting signaling events downstream of JNK activation.
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PMID:Neurotrophic factors prevent ceramide-induced apoptosis downstream of c-Jun N-terminal kinase activation in PC12 cells. 964 62


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