Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Murine embryonic palate mesenchyme (MEPM) cells are responsive to a number of endogenous factors found in the local embryonic tissue environment. Recently, it was shown that activation of the cyclic AMP (cAMP) or the transforming growth factor beta (TGFbeta) signal transduction pathways modulates the proliferative response of MEPM cells to epidermal growth factor (EGF). Since the mitogen-activated protein kinase (MAPK) cascade is a signal transduction pathway that mediates cellular responsiveness to EGF, we examined the possibility that several signaling pathways which abrogate EGF-stimulated proliferation do so via the p42/p44 MAPK signaling pathway. We demonstrate that EGF stimulates MAPK phosphorylation and activity in MEPM cells maximally at 5 minutes. Tyrosine phosphorylation and activation of MAPK was unaffected by treatment of MEPM cells with TGFbeta or cholera toxin. Similarly, TGFbeta altered neither EGF-induced MAPK tyrosine phosphorylation nor activity. However, the calcium ionophore, A23187, significantly increased MAPK phosphorylation which was further increased in the presence of EGF, although calcium mobilization reduced EGF-induced proliferation. Despite the increase in phosphorylation, we could not demonstrate induction of MAPK activity by A23187. Like EGF, phorbol ester, under conditions which activate PKC isozymes in MEPM cells, increased MAPK phosphorylation and activity but was also growth inhibitory to MEPM cells. The MEK inhibitor, PD098059, only partially abrogated EGF-induced phosphorylation. Likewise, depletion of PKC isozymes partially abrogated EGF-induced MAPK phosphorylation. Inhibition of both MEK and PKC isozymes resulted in a marked decrease in MAPK activity, confirming that EGF uses multiple pathways to stimulate MAPK activity. These data indicate that the MAPK cascade does not mediate signal transduction of several agents that inhibit growth in MEPM cells, and that there is a dissociation of the proliferative response and MAP kinase activation. Furthermore, other signaling pathways known to play significant roles in differentiation of palatal tissue converge with the MAPK cascade and may use this pathway in the regulation of alternative cellular processes.
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PMID:Selective modulation of MAP kinase in embryonic palate cells. 964 14

To investigate signaling mechanisms by which hypoxia regulates gene expression, we examined the effect of hypoxia on the cyclic AMP response element-binding protein (CREB) in PC12 cells. Exposure to physiological levels of hypoxia (5% O2, approximately 50 mm Hg) rapidly induced a persistent phosphorylation of CREB on Ser133, an event that is required for CREB-mediated transcriptional activation. Hypoxia-induced phosphorylation of CREB was more robust than that induced by any other stimulus tested, including forskolin, depolarization, and osmotic stress. Furthermore, this effect was not mediated by any of the previously known signaling pathways that lead to phosphorylation of CREB, including protein kinase A, calcium/calmodulin-dependent protein kinase, protein kinase C, ribosomal S6 kinase-2, and mitogen-activated protein kinase-activated protein kinase-2. Hypoxic activation of a CRE-containing reporter (derived from the 5'-flanking region of the tyrosine hydroxylase gene) was attenuated markedly by mutation of the CRE. Thus, a physiological reduction in O2 levels induces a functional phosphorylation of CREB at Ser133 via a novel signaling pathway.
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PMID:Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism. 967 18

Protein kinases catalyse phospho transfer reactions from ATP to serine, threonine or tyrosine residues in target substrates and provide key mechanisms for control of cellular signalling processes. The crystal structures of 12 protein kinases are now known. These include structures of kinases in the active state in ternary complexes with ATP (or analogues) and inhibitor or peptide substrates (e.g. cyclic AMP dependent protein kinase, phosphorylase kinase and insulin receptor tyrosine kinase); kinases in both active and inactive states (e.g. CDK2/cyclin A, insulin receptor tyrosine kinase and MAPK); kinases in the active state (e.g. casein kinase 1, Lck); and kinases in inactive states (e.g. twitchin kinase, calcium calmodulin kinase 1, FGF receptor kinase, c-Src and Hck). This paper summarises the detailed information obtained with active phosphorylase kinase ternary complex and reviews the results with reference to other kinase structures for insights into mechanisms for substrate recognition and control.
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PMID:The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases. 967 85

Extracellular purine nucleotides elicit a diverse range of biological responses through binding to specific cell surface receptors. The ionotrophic P2X subclass of purinoreceptors respond to ATP by stimulation of calcium ion permeability; however, it is unknown how P2X purinoreceptor activation is linked to intracellular signaling pathways. We report that stimulation of PC12 cells with ATP results in the activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 and was wholly dependent upon extracellular calcium ions. Treatment of the cells with adenosine, AMP, ADP, UTP, or alpha,beta-methylene ATP was without effect; however, MAP kinase activation was abolished by pretreatment with suramin and reactive blue 2. The calcium-activated tyrosine kinase, Pyk2, acts as an upstream regulator of the MAP kinases and became tyrosine phosphorylated following treatment of the cells with ATP. We have ruled out the involvement of depolarization-mediated calcium influx because specific blockers of voltage-gated calcium channels did not affect MAP kinase activation. These data provide direct evidence that calcium influx through P2X2 receptors results in the activation of the MAP kinase cascade. Finally, we demonstrate that a different line of PC12 cells respond to ATP through P2Y2 purinoreceptors, providing an explanation for the conflicting findings of purine nucleotide responsiveness in PC12 cells.
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PMID:ATP-stimulated activation of the mitogen-activated protein kinases through ionotrophic P2X2 purinoreceptors in PC12 cells. Difference in purinoreceptor sensitivity in two PC12 cell lines. 968 31

Platelet-derived growth factor (PDGF) stimulates cyclic AMP (cAMP) synthesis in cultured guinea-pig airway smooth muscle (ASM) cells. However, this stimulation is normally countered by the action of cAMP phosphodiesterases. Thus, cAMP synthesis was observed only in cells pre-treated with either 3-isobutyl-1-methylxanthine (IBMX) or with cholera toxin. cAMP synthesis was inhibited by pre-treating cells with well-defined inhibitors of arachidonate metabolite synthesis, such as AACOCF3 [a cytosolic phospholipase A2 (cPLA2) inhibitor] and indomethacin (a cyclooxygenase inhibitor). This suggests that arachidonate metabolites (e.g., prostaglandins) released in response to PDGF stimulate cAMP synthesis. The presence of functional prostaglandin (PG) receptors was confirmed by experiments that showed that exogenous PGE2 stimulated cAMP formation. cPLA2 is regulated by mitogen-activated protein kinase (MAPK) in a number of cell types. The presence of this pathway in ASM cells and its role in regulating arachidonate metabolism were supported by the finding that pre-treatment of cells with PD098059 (an inhibitor of mitogen-activated protein kinase kinase-1 activation) reduced PDGF-stimulated cAMP synthesis. The cAMP formed in response to the arachidonate metabolites subsequently reduced the PDGF-dependent activation of c-Raf, MAPK, and DNA synthesis, suggesting the presence of a negative feedback pathway.
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PMID:PDGF-stimulated cyclic AMP formation in airway smooth muscle: assessment of the roles of MAP kinase, cytosolic phospholipase A2, and arachidonate metabolites. 969 80

We determined whether resveratrol, a phenolic antioxidant found in grapes and other food products, inhibited phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induces COX-2 and causes a marked increase in the production of prostaglandin E2. These effects were inhibited by resveratrol. Resveratrol suppressed PMA-mediated increases in COX-2 mRNA and protein. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by resveratrol. PMA caused about a 6-fold increase in COX-2 promoter activity, which was suppressed by resveratrol. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, indicated that the effects of PMA and resveratrol were mediated via a cyclic AMP response element. Resveratrol inhibited PMA-mediated activation of protein kinase C. Overexpressing protein kinase C-alpha, ERK1, and c-Jun led to 4.7-, 5.1-, and 4-fold increases in COX-2 promoter activity, respectively. These effects also were inhibited by resveratrol. Resveratrol blocked PMA-dependent activation of AP-1-mediated gene expression. In addition to the above effects on gene expression, we found that resveratrol also directly inhibited the activity of COX-2. These data are likely to be important for understanding the anti-cancer and anti-inflammatory properties of resveratrol.
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PMID:Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. 970 26

c-jun proto-oncogene expression is extinguished in cells transformed by v-Jun; however, the mechanistic basis of this phenomenon has not been elucidated. c-jun mRNA levels are greatly reduced in v-Jun-transformed cells, and we show that this reduction is associated with a similar decrease in the rate of c-jun transcription. Transcriptional down-regulation was also evident in functional assays in which the c-jun gene promoter was approximately 10-fold less active in v-Jun-transformed cells than it was in normal cells. This reduction was largely attributable to a conserved 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE)-like motif at position -72 (the proximal junTRE) that was essential for efficient basal expression in normal cells but that conferred little, if any, detectable transcriptional activity in v-Jun-transformed cells. DNA-binding analysis showed that this element was recognized by a mixture of c-Jun/Fra and cyclic AMP-responsive element-binding protein/activating transcription factor-like complexes in normal cells but that v-Jun/Fra heterodimers predominated in v-Jun-transformed cells. Furthermore, ectopic expression of v-Jun repressed c-jun promoter activity in normal cells through the proximal junTRE. Thus, the deficit in transcription mediated by the junTRE correlates with and is most likely attributable to binding of v-Jun to this element in vivo. We also find that the c-jun promoter is refractory to induction via the stress-activated protein kinase/c-jun NH2-terminal kinase pathway in v-Jun-transformed cells, suggesting that v-Jun interferes with signal-regulated gene expression. Therefore, c-jun is an example of a cellular gene, the transcription of which is regulated negatively by v-Jun in vivo.
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PMID:v-Jun represses c-jun proto-oncogene expression in vivo through a 12-O-tetradecanoylphorbol-13-acetate-responsive element in the proximal gene promoter. 971 84

Little is known about the coupling of serotonin 5-HT1B receptors to cellular signals other than cyclic AMP. In the present studies, the activation by 5-HT1B receptors of p70 S6 kinase and the mitogen-activated protein kinase (MAP kinase) ERK-2 was investigated. Studies were performed by using both nontransfected Chinese hamster ovary (CHO) cells, which express endogenous receptors at a very low density, and a stable transfected CHO cell line expressing 5-HT1B receptors at 230 fmol/mg of membrane protein, a density similar to that expressed in cortex. In nontransfected cells, 5-HT was found to stimulate a greater than twofold increase in MAP kinase activity with an EC50 of 20 nM. Reflecting increased density of receptors, 5-HT caused a greater than eightfold activation of ERK-2 in transfected cells with an EC50 of 2 nM. 5-HT was found to also stimulate p70 S6 kinase in both nontransfected and transfected cells. The stimulation was sixfold in both types of cells, but the EC50 for 5-HT was fourfold lower in transfected cells. The coupling of 5-HT1B receptors to ERK-2 and to p70 S6 kinase was inhibited by pertussis toxin, inhibitors of phosphatidylinositol 3-kinase, and by the inhibitor of MAP kinase kinase PD098059. Activation of p70 S6 kinase, but not ERK-2, was also inhibited by rapamycin. These findings demonstrate that 5-HT1B receptors couple to ERK-2 and p70 S6 kinase through overlapping, but nonidentical, pathways.
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PMID:Coupling of serotonin 5-HT1B receptors to activation of mitogen-activated protein kinase (ERK-2) and p70 S6 kinase signaling systems. 972 30

Proliferation of myofibroblastic hepatic stellate cells (HSC) in response to growth factors is essential for the development of liver fibrosis. We have reported that prostaglandins (PG) and cyclic AMP (cAMP) inhibit growth of human HSC. This PG/cAMP pathway transduces the endothelin (ET) B-mediated antiproliferative effect of endothelin-1 (ET-1) and up-regulates ETB receptors. Here, we show that platelet-derived growth factor (PDGF)-BB and thrombin, although mitogenic, generate growth inhibitory PGE2 in myofibroblastic human HSC. The two peptides elicit early PGE2 and cAMP synthesis, and also promote delayed induction of cyclooxygenase (COX)-2. Both early and delayed production of PGE2 counteract the mitogenic effect of PDGF-BB and thrombin because: (i) pretreatment with the COX inhibitor ibuprofen markedly enhances the mitogenic effect of both peptides; (ii) blocking early synthesis of PGE2 greatly enhances extracellular signal-regulated kinase (ERK) activation by both growth factors; (iii) enhancement of DNA synthesis by ibuprofen is only lost when the inhibitor is added after COX-2 induction has occurred. Finally, PDGF-BB and thrombin raise ETB receptors through the PG pathway. Thus, ibuprofen blunts growth factor-induced increase in ETB receptors. Up-regulation of the growth inhibitory ETB receptors by both mitogens may enhance the antiproliferative effect of ET-1 and thereby establish a negative feedback of their mitogenic effect. Our results shed light on novel growth inhibitory signals evoked by two mitogenic growth factors expressed during liver injury.
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PMID:Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors. 976 55

A peptide corresponding to the epidermal growth factor homology domain of beta-heregulin stimulated autophosphorylation of the heregulin receptors erbB2 and erbB3 in Schwann cells and activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. Heregulin-dependent activation of PAK65, a component of the stress-activated signaling pathway, ribosomal S6 kinase, and a cyclic AMP (cAMP) response element binding protein (CREB) kinase, identified as p95(RSK2), was also observed. Receptor phosphorylation and activation of these kinases in response to heregulin occurred in the absence of forskolin stimulation and were not augmented in cells treated with forskolin, a direct activator of adenylyl cyclase. Schwann cell proliferation in response to heregulin was observed only when the cells were also exposed to an agent that elevates cAMP levels. In the absence of heregulin, elevation of cAMP levels failed to stimulate Schwann cell proliferation. Forskolin significantly enhanced heregulin-stimulated expression of cyclin D and phosphorylation of the retinoblastoma gene product. In cells treated with both heregulin and forskolin there was a sustained accumulation of phospho-CREB, which was not observed in cells treated with either agent alone. Heregulin and forskolin synergistically activated transcription of a cyclin D promoter construct. These results demonstrate that heregulin-stimulated activation of MAP kinase is not sufficient to induce maximal Schwann cell proliferation. Expression of critical cell cycle regulatory proteins and cell division require activation of both heregulin and cAMP-dependent processes.
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PMID:Synergistic regulation of Schwann cell proliferation by heregulin and forskolin. 977 41


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