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)

Prostanoids are arachidonic acid metabolites and are generally accepted to play pivotal functions in amongst others inflammation, platelet aggregation, and vasoconstriction/relaxation. Inhibition of their production with, for instance, aspirin has been used for over a century to combat a large variety of pathophysiological processes, with great clinical success. Hence, the cellular changes induced by prostanoids have been subject to an intensive research effort and especially prostanoid-dependent signal transduction has been extensively studied. In this review, we discuss the impact of the five basic prostanoids, TxA(2), PGF(2alpha), PGE(2), PGI(2), and PGD(2), via their receptors on cellular physiology. These inflammatory lipids may stimulate serpentine plasma membrane-localized receptors, which in turn affect major signaling pathways, such as the MAP kinase pathway and the protein kinase A pathway, finally resulting in altered cellular physiology. In addition, prostanoids may activate the PPARgamma members of the steroid/thyroid family of nuclear hormone receptors, which act as transcription factors and may thus directly influence gene transcription. Finally, evidence exists that prostanoids act as second messengers downstream of mitogen receptor activation, mediating events, such as cytoskeletal changes, maybe via direct interaction with GTPase activating proteins. The final cellular reaction to prostaglandin stimulation will most likely depend on combined effects of the above-mentioned levels of interaction between prostaglandins and their cellular receptors.
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PMID:Prostanoids and prostanoid receptors in signal transduction. 1510 66

Several agonists acting on G protein-coupled receptors (GPCR) enhance the mitogenic effect of epidermal growth factor (EGF) in rat hepatocytes, through mechanisms that have only partially been clarified. Results in various cells have led to the idea that a major mechanism for GPCR-mediated stimulation of cell growth is transactivation of receptor tyrosine kinases, particularly the EGF receptor (EGFR), leading to rapid phosphorylation of the EGFR and activation of downstream signaling pathways. In the present study cultured rat hepatocytes were exposed to various GPCR agonists, including vasopressin, angiotensin II (Ang.II), norepinephrine, or prostaglandin F(2 alpha) (PGF(2 alpha)). None of these agents increased the phosphorylation of the EGFR or the docking protein Shc. Furthermore, we examined the effect of the GPCR agonists on the expression of two early response genes believed to be involved in growth activation. The GPCR agonists increased the mRNA expression of c-myc, and also of activating transcription factor 3 (ATF3)/liver regeneration factor-1 (LRF-1), which is a novel finding. Finally, the selective EGFR inhibitor AG1478 did not suppress the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) or the induction of c-myc or ATF3/LRF-1 by the GPCR agonists, and did not prevent the comitogenic effects induced by these agents, while it blocked the effect of EGF on these responses. The results suggest that GPCR agonists induce expression of ATF3/LRF-1 and c-myc and exert comitogenic effects through mechanisms that do not require EGFR transactivation.
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PMID:G protein-coupled receptor agonist-stimulated expression of ATF3/LRF-1 and c-myc and comitogenic effects in hepatocytes do not require EGF receptor transactivation. 1538 57

The purpose of this study was to explore the involvement of adenosine receptor(s) in porcine coronary artery (PCA) relaxation and to define the role of MAPK signaling pathways. Isometric tensions were recorded in denuded PCA rings. 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine receptor agonist, induced a concentration-dependent relaxation (EC(50) = 16.8 nM) of PGF(2alpha) (10 microM)-preconstricted arterial rings. NECA-induced relaxation was completely blocked by 0.1 microM SCH-58261 (A(2A) antagonist) at lower doses (1-40 nM) but not at higher doses (80-1,000 nM). MRS-1706 (1 microM, A(2B) antagonist) was able to shift the NECA concentration-response curve to the right. CGS-21680 (selective A(2A) agonist) induced responses similarly to NECA, whereas N(6)-cyclopentyladenosine (A(1) agonist) and Cl-IB-MECA (A(3) agonist) did not. Furthermore, the effect of NECA was attenuated by the addition of SB-203580 (10 microM, p38 MAPK inhibitor) but not by PD-98059 (10 microM, MEK inhibitor). Interestingly, SB-203580 had no effect on CGS-21680-induced relaxation. Western blot analysis demonstrated that PGF(2alpha) and adenosine agonists stimulated p38 MAPK at a concentration of 40 nM in PCA smooth muscle cells. MRS-1706 (1 microM) significantly reduced NECA-induced p38 MAPK phosphorylation. Addition of NECA and SB-203580 alone or in combination inhibited PGF(2alpha)-induced p38 MAPK. Western blot data were further confirmed by p38 MAPK activity measurement using activating transcription factor-2 assay. Our results suggest that the adenosine receptor subtype involved in causing relaxation of porcine coronary smooth muscle is mainly A(2A) subtype, although A(2B) also may play a role, possibly through p38 MAPK pathway.
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PMID:Involvement of p38-mitogen-activated protein kinase in adenosine receptor-mediated relaxation of coronary artery. 1565 66

We have previously reported that prostaglandin F(2alpha) (PGF(2alpha)) and its selective agonist fluprostenol increase basic fibroblast growth factor (FGF-2) mRNA and protein production in osteoblastic Py1a cells. The present report extends our previous studies by showing that Py1a cells express FGF receptor-2 (FGFR2) and that treatment with PGF(2alpha) or fluprostenol decreases FGFR2 mRNA. We have used confocal and electron microscopy to show that, under PGF(2alpha) stimulation, FGF-2 and FGFR2 proteins accumulate near the nuclear envelope and colocalize in the nucleus of Py1a cells. Pre-treatment with cycloheximide blocks nuclear labelling for FGF-2 in response to PGF(2alpha). Treatment with SU5402 does not block prostaglandin-mediated nuclear internalization of FGF-2 or FGFR2. Various effectors have been used to investigate the signal transduction pathway. In particular, pre-treatment with phorbol 12-myristate 13-acetate (PMA) prevents the nuclear accumulation of FGF-2 and FGFR2 in response to PGF(2alpha). Similar results are obtained by pre-treatment with the protein kinase C (PKC) inhibitor H-7. In addition, cells treated with PGF(2alpha) exhibit increased nuclear labelling for the mitogen-activated protein kinase (MAPK), p44/ERK2. Pre-treatment with PMA blocks prostaglandin-induced ERK2 nuclear labelling, as confirmed by Western blot analysis. We conclude that PGF(2alpha) stimulates nuclear translocation of FGF-2 and FGFR2 by a PKC-dependent pathway; we also suggest an involvement of MAPK/ERK2 in this process.
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PMID:Prostaglandins differently regulate FGF-2 and FGF receptor expression and induce nuclear translocation in osteoblasts via MAPK kinase. 1565 55

We have previously reported that prostaglandin F2alpha (PGF2alpha) activates p44/p42 mitogen-activated protein (MAP) kinase through protein kinase C (PKC), resulting in the synthesis of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells, and that incadronate, a bisphosphonate, amplifies the VEGF synthesis. In the present study, we investigated the effects of tiludronate and etidronate, other bisphosphonates, on the PGF2alpha-stimulated VEGF synthesis in these cells. Tiludronate reduced the synthesis of VEGF induced by PGF2alpha. The PGF(2alpha)-stimulated phosphorylation of p44/p42 MAP kinase was suppressed by tiludronate. On the other hand, etidronate affected neither the VEGF synthesis nor the phosphorylation of p44/p42 MAP kinase elicited by PGF2alpha. Tiludronate attenuated the phosphorylation of both Raf-1 and MEK1/2 induced by PGF2alpha. The VEGF synthesis stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of PKC, was suppressed by tiludronate. The TPA-induced phosphorylations of Raf-1, MEK1/2 and p44/p42 MAP kinase were inhibited by tiludronate. These results strongly suggest that tiludronate but not etidronate suppresses the PGF2alpha-stimulated VEGF synthesis in osteoblasts, and that the effect of tiludronate is exerted at the point between PKC and Raf-1.
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PMID:Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1592 88

The mechanisms through which p38 mitogen-activated protein kinase (p38 MAPK) is involved in smooth muscle contraction remain largely unresolved. We examined the role of p38 MAPK in prostaglandin F(2alpha) (PGF(2alpha))-induced vasoconstriction and in hypoxic pulmonary vasoconstriction (HPV) of rat small intrapulmonary arteries (IPA). The p38 MAPK inhibitors SB-203580 and SB-202190 strongly inhibited PGF(2alpha)-induced vasoconstriction, with IC(50)s of 1.6 and 1.2 microM, whereas the inactive analog SB-202474 was approximately 30-fold less potent. Both transient and sustained phases of HPV were suppressed by SB-203580, but not by SB-202474 (both 2 microM). Western blot analysis revealed that PGF(2alpha) (20 microM) increased phosphorylation of p38 MAPK and of heat shock protein 27 (HSP27), and this was abolished by SB-203580 but not by SB-202474 (both 2 microM). Endothelial denudation or blockade of endothelial nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly suppressed the relaxation of PGF(2alpha)-constricted IPA by SB-203580, but not by SB-202474. Similarly, the inhibition of HPV by SB-203580 was prevented by prior treatment with L-NAME. SB-203580 (2 microM), but not SB-202474, enhanced relaxation-induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP) in endothelium-denuded IPA constricted with PGF(2alpha). In alpha-toxin-permeabilized IPA, SB-203580-induced relaxation occurred in the presence but not the absence of the NO donor sodium nitroprusside (SNP); SB-202474 was without effect even in the presence of SNP. In intact IPA, neither PGF(2alpha)- nor SNAP-mediated changes in cytosolic free Ca(2+) were affected by SB-203580. We conclude that p38 MAPK contributes to PGF(2alpha)- and hypoxia-induced constriction of rat IPA primarily by antagonizing the underlying Ca(2+)-desensitizing actions of NO.
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PMID:Modulation of PGF2alpha- and hypoxia-induced contraction of rat intrapulmonary artery by p38 MAPK inhibition: a nitric oxide-dependent mechanism. 1605 81

Prostaglandin F(2alpha) (PGF(2alpha)) is a vasoactive factor that causes constriction and hypertrophy of vascular smooth muscle cells (VSMCs). However, the mechanism of PGF(2alpha)-induced hypertrophy is largely unknown. Cyclic AMP-response element (CRE)-binding protein (CREB), the best characterized stimulus-induced transcription factor, activates transcription of target genes with CRE and promotes cell growth. We examined the role of CREB in PGF(2alpha)-induced hypertrophy of VSMCs. PGF(2alpha) induced phosphorylation of CREB at serine 133, which is a critical marker of activation, after 5-10min of stimulation in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase and p38 mitogen-activated protein kinase (p38-MAPK) suppressed PGF(2alpha)-induced CREB phosphorylation. Inhibition of epidermal growth factor receptor (EGFR) and mitogen- and stress-activated protein kinase-1 also suppressed PGF(2alpha)-induced CREB phosphorylation. Overexpression of dominant-negative form of CREB (AdCREB M1), of which serine 133 was replaced with alanine, inhibited PGF(2alpha)-induced c-fos mRNA expression as well as hypertrophy of VSMCs [hypertrophy index (microg/10(4)cell); control 8.13, PGF(2alpha) 9.85, AdCREB M1 7.91, and AdCREB M1+PGF(2alpha) 8.43]. These results suggest that PGF(2alpha) activated CRE-dependent gene transcription through EGFR transactivation, and the CREB pathway plays a critical role in PGF(2alpha)-induced hypertrophy of VSMCs.
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PMID:cAMP-response element-binding protein mediates prostaglandin F2alpha-induced hypertrophy of vascular smooth muscle cells. 1624 6

Fluid percussion brain injury elevates the cerebrospinal fluid (CSF) concentration of the opioid nociceptin/orphanin FQ (N/OFQ), which potentiates vasoconstriction to the prostaglandins U 46619, a thromboxane A(2) mimic, and prostaglandin (PG)F(2a). This study investigated the role of the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) isoforms of mitogen activated protein kinase (MAPK) in potentiated prostaglandin vasoconstriction after brain injury and the relationship of brain injury induced release of N/OFQ to MAPK. Pial artery diameter was measured with a video microscaler by observation through a glass coverslip cranial window placed in the parietal cortex of newborn pigs. Brain injury potentiated U 46619 induced pial artery vasoconstriction but U 0126 and SB 203580 (10(-6) and 10(-5) M, respectively) (ERK and p38 MAPK inhibitors) blocked the potentiation. In contrast, administration of SP 600125 (10(-6) and 10(-5) M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI. Co-administration of N/OFQ (10(-10) M), the CSF concentration observed after brain injury, with U 46619 or PGF(2a) under non brain injury conditions potentiated prostaglandin vasoconstriction but U 0126 and SB 203580 blocked such potentiation. Administration of SP 600125 modestly attenuated prostaglandin potentiation by N/OFQ. These data show that activation of ERK and p38 primarily contribute to potentiation of prostaglandin constriction after brain injury. These data suggest that N/OFQ differentially activates ERK, p38, and JNK MAPK to contribute to potentiated prostaglandin vasoconstriction after fluid percussion brain injury.
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PMID:Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury. 1635 4

Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (overdistension of the lung) triggers a proinflammatory response. Along with cytokines, inflammatory mediators such as bioactive lipids are involved in the regulation of the inflammatory response. The arachidonic acid pathway is a key source of bioactive lipid mediators, including prostanoids. Although ventilation has been shown to influence the production of prostanoids in the lung, the mechanotransduction pathways are unknown. Herein, we established that cyclic stretch of fetal lung epithelial cells, but not fibroblasts, can evoke an extremely sensitive, rapid alteration in eicosanoid metabolism through a cyclooxygenase (COX)-2 dependent mechanism. Cyclic stretch significantly increased PGI(2), PGF(2alpha), PGD(2), PGE(2), and thromboxane B(2) levels in the media of epithelial cells, but did not alter leukotriene B(4) or 12-hydroxyeicosatetraenoic acid levels. Inhibition of COX-2, but not COX-1, attenuated the cyclic stretch-induced PG increase in the media, suggesting that cyclic stretch primarily affected PG synthesis. Substrate (free arachidonic acid) availability for PG generation was increased because of a cyclic stretch-induced activation of cytosolic phospholipase A(2) (cPLA(2)) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA(2) and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.
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PMID:Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells. 1660 90

In our previous study, we showed that prostaglandin F2alpha (PGF2alpha) stimulates vascular endothelial growth factor (VEGF) synthesis via activation of p44/p42 mitogen-activated protein (MAP) kinase via protein kinase C (PKC) in osteoblast-like MC3T3-E1 cells. In addition, we demonstrated that incadronate amplified, and tiludronate suppressed PGF2alpha-induced VEGF synthesis among bisphosphonates, while alendronate or etidronate had no effect. In the present study, we investigated the effects of minodronate, a newly developed bisphosphonate, on PGF (2alpha)-induced VEGF synthesis in MC3T3-E1 cells. Minodronate significantly reduced VEGF synthesis induced by PGF2alpha dose-dependently at levels between 3 and 100 microM. PGF2alpha-stimulated phosphorylation of Raf-1, MEK1/2 and p44/p42 MAP kinase were suppressed by minodronate. 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator VEGF synthesis induced by PKC, was inhibited by minodronate. Minodronate inhibited Raf-1, MEK1/2 and p44/p42 MAP kinase phosphorylation induced by TPA. Mevalonate failed to affect the suppressive effect of minodronate on PGF2alpha-induced VEGF synthesis. Taken together, these results indicate that minodronate suppresses PGF2alpha-stimulated VEGF synthesis at the point between PKC and Raf-1 in osteoblasts.
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PMID:Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts. 1667 5


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