Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of interleukin (IL) on intracellular free Ca2+ concentration ([Ca2+]i) rise and catecholamine (CA) release were examined in isolated, cultured bovine adrenal chromaffin cells. IL-1alpha and IL-1beta inhibited the rise of [Ca2+]i and CA release induced by acetylcholine (ACh) and excess KCl both in normal and in Ca2+-sucrose medium. Pretreatment by IL-1 receptor antagonist (IL-1RA) blocked the inhibitory actions of IL-1alpha. IL-1alpha reduced CA release induced by veratridine in normal medium but not in the presence of diltiazem. Analysis using specific blockers for voltage-operated Ca2+ channels (VOCC) revealed that IL-1alpha and IL-1beta specifically inhibited the P/Q-type Ca2+ channel to reduce [Ca2+]i rise induced by excess KCl. IL-1 did not affect [Ca2+]i rise induced either by bradykinin or caffeine in Ca2+-deprived medium or via activation of store-operated Ca2+ channel (SOC). The inhibitory effects of IL-1alpha were blocked by pretreatments with herbimycin A, U0126 and PD 98054, but not with SB202190, SP 600125 or pertussis toxin (PTX). These results demonstrated that IL-1 inhibits stimulation-evoked [Ca2+]i rise and CA release in chromaffin cells by blocking voltage-operated P/O-type Ca2+ channels. The inhibitory action of IL-1 may be mediated through the tyrosine kinase and MEK/ERK pathways.
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PMID:Interleukin-1 inhibits voltage-dependent P/Q-type Ca2+ channel associated with the inhibition of the rise of intracellular free Ca2+ concentration and catecholamine release in adrenal chromaffin cells. 1527 87

We report here that apelin (65-77) activates p70 S6 kinase (p70S6K), not only in CHO cells that have been stably transfected with the apelin receptor, but also in umbilical endothelial cells (HUVEC), which express it endogenously. Apelin (65-77) induces a time-dependent phosphorylation of p70S6K at residues T421/S424 and T389. This dual phosphorylation is associated with two transduction cascades, involving a PI3K pathway and an ERK pathway, respectively. The PI3K pathway, which can be blocked by wortmannin, leads to phosphorylation of Akt at residues T308 or S473, which then promotes the phosphorylation of p70S6K at T421/S424 and T389. The ERK pathway is blocked by PD 098059, a MEK inhibitor, and results in the phosphorylation of p70S6K at T421/S424. Phosphorylation both of Akt and p70S6K is abrogated by pretreatment with pertussis toxin (PTX) and an inhibitor of atypical PKCs. In addition, we demonstrate that apelin (65-77) also increases the enzymatic activity of p70S6K and that the effects of the previously mentioned inhibitors on the level of T389 phosphorylation correlate with their action on enzyme activity. Interestingly, the main findings were reproduced in umbilical endothelial cells and apelin (65-77) promoted thymidine incorporation into DNA of these cells, revealing that apelin is a new mitogenic peptide for the endothelial cell.
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PMID:Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. 1538 34

We showed previously that activation of the thromboxane prostanoid (TP) receptor causes human airway smooth muscle (HASM) cells to proliferate, suggesting a role in airway remodeling. This study aimed at determining the molecular mechanisms underlying this mitogenic action. We found that the MEK inhibitor PD98059 significantly affected agonist-induced DNA synthesis of HASM cells, which suggests that extracellular signal-regulated kinases (ERK) are involved. ERK activation by the agonist U46619 was rapid, sensitive to pertussis toxin, and significantly abrogated by the tyrosine kinase inhibitors genistein and PP1. Stimulation of the TP receptor was also found to translocate phosphorylated ERK into the nucleus. TP receptor was found to activate Ras, as demonstrated by inhibition of ERK activation and DNA synthesis by Clostridium sordellii lethal toxin, and by the ability of U46619 to increase RasGTP. Finally, [(3)H]thymidine incorporation and ERK phosphorylation were also affected by prior treatment with protein kinase C inhibitor GF109203X, although to different extents. In conclusion, in HASM cells TP receptor, predominantly coupled to G(i/o) proteins, activates the Ras/ERK pathway to induce mitogenesis, probably with the involvement of nonreceptor tyrosine kinases and protein kinase C.
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PMID:Thromboxane prostanoid receptor signals through Gi protein to rapidly activate extracellular signal-regulated kinase in human airways. 1562 72

We recently reported the use of a gene-trapping approach to isolate cell clones in which a reporter gene had integrated into genes modulated by T-cell activation. We have now tested a panel of clones from that report and identified the one that responds to a variety of G-protein coupled receptors (GPCR). The beta-lactamase tagged EGR-3 Jurkat cell was used to dissect specific GPCR signaling in vivo. Three GPCRs were studied, including the chemokine receptor CXCR4 (Gi-coupled) that was endogenously expressed, the platelet activation factor (PAF) receptor (Gq-coupled), and beta2 adrenergic receptor (Gs-coupled) that was both stably transfected. Agonists for each receptor activated transcription of the beta-lactamase tagged EGR-3 gene. Induction of EGR-3 through CXCR4 was blocked by pertussis toxin and PD58059, a specific inhibitor of MEK (MAPK/ERK kinase). Neither of these inhibitors blocked isoproterenol or PAF-mediated activation of EGR-3. Conversely, beta2- and PAF-mediated EGR-3 activation was blocked by the p38, specific inhibitor SB580. In addition, both beta2- and PAF-mediated EGR-3 activation could be synergistically activated by CXCR4 activation. This combined result indicates that EGR-3 can be activated through distinct signal transduction pathways by different GPCRs and that signals can be integrated and amplified to efficiently tune the level of activation.
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PMID:Integration of G-protein coupled receptor signaling pathways for activation of a transcription factor (EGR-3). 1562 29

Somatostatin (SST) controls the proliferation of a variety of cell types. Its effects are mediated by five G protein-coupled receptors (SSTR1-SSTR5), variably expressed in normal and cancer tissues. SST inhibition of cell proliferation can be exploited by both direct and indirect mechanisms: the main direct pathway involves the modulation of phosphotyrosine phosphatase (PTP) activity. Here we show that SST cytostatic activity is mediated by the activation of a receptor-like PTP, named PTPeta. The role of this PTP in the antiproliferative activity of SST in five glioma cell lines (C6, U87MG, U373MG, DBTRG05MG, and CAS1) and in four postsurgical human glioblastoma specimens, has been studied. SST inhibited growth only in C6 and U87MG that express PTPeta. In C6 cells, SST antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate, indicating the involvement of G proteins and PTPs. The role of PTPeta in the SST inhibitory effects was demonstrated by testing the PTPeta activity: it was increased by SST treatment and paralleled by inhibition of ERK1/2 activation. Since basic fibroblast growth factor-dependent MEK phosphorylation was not affected by SST, we propose a direct effect of SST-activated PTPeta on ERK1/2 phosphorylation. Finally, the SSTR mRNAs were identified in all of the 36 gliomas analyzed, whereas PTPeta expression was found in 33% of cases. Culturing four gliomas, a precise correlation between the expression of PTPeta and the SST antiproliferative effects was identified. In conclusion, in glioma cells, SST antiproliferative activity requires the expression and activation of PTPeta, which directly dephosphorylates ERK1/2.
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PMID:The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of ERK1/2. 1565 6

Neurotrophic growth factors are involved in cell survival. However, natural growth factors have a very limited therapeutic use because of their short half-life. In the present study, we investigated the mechanism of action of a non-peptidic neurotrophic drug, Xaliproden, a potential molecule for the treatment of motoneuron diseases, since the transduction pathways of this synthetic 5-HT1A agonist are very poorly understood. Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the ERK1 and ERK2 isoforms of MAP kinase, which then rapidly decrease to the basal level. We demonstrate that isoforms of the SHC adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced MAP kinases activation. The inhibitor of Ras farnesylation, FPT-1, and the protein kinase C inhibitors, GF 109203X and chelerythrine, inhibited the Xaliproden-induced MAP kinase activation, suggesting p21Ras and PKC involvement. Moreover, the observations that the 5-HT1A antagonist, pindobind, and pertussis toxin abolished the Xaliproden-induced ERK stimulation suggested that Xaliproden activates the MAP kinase pathways by stimulating the G protein-coupled receptor, 5-HT1A. These results demonstrate clearly that the non-peptidic compound, Xaliproden, exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins. These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by MAP kinase pathway by a pertussis toxin-sensitive mechanism involving 5-HT1A receptors, p21 Ras and MEK-1 and by PKC and Akt pathways.
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PMID:Xaliproden (SR57746A) induces 5-HT1A receptor-mediated MAP kinase activation in PC12 cells. 1588 46

CART peptides are important neurotransmitters, but little is known about their receptors or signaling pathways in cells. In this study we describe the effects of CART 55-102 on the stimulation of extracellular signal-related kinase (ERK) in a pituitary-derived cell line. CART 55-102 treatment resulted in markedly enhanced ERK phosphorylation in AtT20 and GH3 cells, but had no significant effect on ERK phosphorylation levels in a variety of other cell types that were examined. The peptide activated ERK1 and 2 in AtT20 cells in a dose- and time-dependent manner, but an inactive peptide, CART 1-27, had no effect. U0126, an inhibitor of the MEK kinases, blocked the CART-stimulated activation of ERKs. ERK activation was also attenuated by pertussis toxin pre-treatment, but not by genistein, suggesting a Gi/o-dependent mechanism. Overall, these data strongly support the existence of a specific receptor for CART peptide that is a G-protein coupled receptor utilizing a Gi/o mechanism involving MEK1 and 2.
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PMID:Cocaine- and amphetamine-regulated transcript (CART) peptide activates the extracellular signal-regulated kinase (ERK) pathway in AtT20 cells via putative G-protein coupled receptors. 1590 20

Lipoxins (LX) are arachidonic acid metabolites able to induce monocyte chemotaxis in vitro and in vivo. Nonetheless, the signaling pathways mediating this process are yet unclear. In this study, we have investigated the mechanisms associated with human monocyte activation in response to 15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATL-1), a stable 15-epi-LXA4 analog. Our results demonstrate that ATL-1-induced monocyte chemotaxis (10-300 nM) is inhibited by pertussis toxin, suggesting an effect via the G-protein-linked LXA4 receptor. Monocytes stimulated with the analog presented an increased ERK-2 phosphorylation, which was reduced by PD98059, a selective inhibitor of the MEK 1/2 pathway. After exposure of the cells to ATL-1, myosin L chain kinase (MLCK) phosphorylation was evident and this effect was inhibited by PD98059 or Y-27632, a specific inhibitor of Rho kinase. In addition, Y-27632 abolished ERK-2 activation, suggesting that the MAPK pathway is downstream of Rho/Rho kinase in MLCK activation induced by ATL-1. The specific MLCK inhibitor ML-7, as well as Y-27632, abrogated monocyte chemotaxis stimulated by the analog, confirming the central role of the Rho kinase/MLCK pathway on ATL-1 action. Together, these results indicate that ATL-1 acts as a potent monocyte chemoattractant via Rho kinase and MLCK. The present study clarifies some of the mechanisms involved on the activation of monocytes by LXs and opens new avenues for investigation of these checkpoint controllers of inflammation.
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PMID:Involvement of the Rho-kinase/myosin light chain kinase pathway on human monocyte chemotaxis induced by ATL-1, an aspirin-triggered lipoxin A4 synthetic analog. 1603 27

We have previously identified a Galpha(i/o)-protein-coupled receptor (TG1019/OXE) using 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) as its ligand. We investigated signal transduction from TG1019 following stimulation with 5-oxo-ETE and role of TG1019 in 5-oxo-ETE-induced chemotaxis, using Chinese hamster ovary cells expressing TG1019 (CHO/TG1019 cells). 5-Oxo-ETE induced intracellular calcium mobilization and rapid activation of MEK/ERK and PI3K/Akt pathways in CHO/TG1019 cells. CHO/TG1019 cells stimulated with 5-oxo-ETE and other eicosanoids exhibited chemotaxis with efficacies related to agonistic activity of each eicosanoid for TG1019. Pretreatment of the cells with pertussis toxin, a phospholipase C (PLC) inhibitor (U73122) or a PI3K inhibitor (LY294002), markedly suppressed 5-oxo-ETE-induced chemotaxis, whereas pretreatment with a MEK inhibitor (PD98059) had no significant effect on the chemotaxis. Our results show that TG1019 mediates 5-oxo-ETE-induced chemotaxis and that signals from TG1019 are transduced via Galpha(i/o) protein to PLC/calcium mobilization, MEK/ERK, and PI3K/Akt, among which PLC and PI3K would play important roles in the chemotaxis.
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PMID:TG1019/OXE, a Galpha(i/o)-protein-coupled receptor, mediates 5-oxo-eicosatetraenoic acid-induced chemotaxis. 1603 85

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2'-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.
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PMID:Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. 1604 62


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