UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of pertussis toxin (PTX)-sensitive and -insensitive pathways in the activation of the mitogen-activated protein kinase (MAPK) cascade was examined in ventricular cardiomyocytes cultured from neonatal rats. A number of agonists that activate heterotrimeric G-protein-coupled receptors stimulated MAPK activity after exposure for 5 min. These included foetal calf serum (FCS), endothelin-1 (these two being the most effective of the agonists examined), phenylephrine, endothelin-3, lysophosphatidic acid, carbachol, isoprenaline and angiotensin II. Activation of MAPK and MAPK kinase (MEK) by carbachol returned to control levels within 30-60 min, whereas activation by FCS was more sustained. FPLC on Mono Q showed that carbachol and FCS activated two peaks of MEK and two peaks of MAPK (p42MAPK and p44MAPK). Pretreatment of cells with PTX for 24 h inhibited the activation of MAPK by carbachol, FCS and lysophosphatidic acid, but not that by endothelin-1, phenylephrine or isoprenaline. Involvement of G-proteins in the activation of the cardiac MAPK cascade was demonstrated by the sustained (PTX-insensitive) activation of MAPK (and MEK) after exposure of cells to AlF4-. AlF4- activated PtdIns hydrolysis, as did endothelin-1, endothelin-3, phenylephrine and FCS. In contrast, the effect of lysophosphatidic acid on PtdIns hydrolysis was small and carbachol was without significant effect even after prolonged exposure. We conclude that PTX-sensitive (i.e. Gi/G(o)-linked) and PTX-insensitive (i.e. Gq/Gs-linked) pathways of MAPK activation exist in neonatal ventricular myocytes. FCS may stimulate the MAPK cascade through both pathways.
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PMID:Activation of the mitogen-activated protein kinase cascade by pertussis toxin-sensitive and -insensitive pathways in cultured ventricular cardiomyocytes. 762 7

Angiotensin II has been demonstrated to act as a growth factor in rat cardiac fibroblasts. However, the signaling events that lead to fibroblast cell growth in response to angiotensin II remain to be elucidated. This study was designed to determine whether angiotensin II stimulated tyrosine phosphorylation of proteins in cardiac fibroblasts. Immunoblot analysis demonstrated rapid tyrosine phosphorylation of distinct substrates of 125, 95, 46-60, and 44 kDa in response to 10 nM angiotensin II. Tyrosine phosphorylation was maximal at 5 min and persisted for at least 180 min. Additional tyrosine-phosphorylated proteins of 185, 145, and 85 kDa were detected in response to 10 ng/ml platelet-derived growth factor BB. A cluster of 75-80-kDa proteins were phosphorylated in response to angiotensin II, phorbol ester, and platelet-derived growth factor. Angiotensin II-induced tyrosine phosphorylation was unaffected by phorbol ester-sensitive protein kinase C down-regulation and could be partially blocked by pertussis toxin pretreatment. Angiotensin II stimulation resulted in increased cytosolic tyrosine kinase activity which was recovered by immunoprecipitation. Immunoblot analysis demonstrated tyrosine phosphorylation of p44MAPK, and, in addition, we demonstrated for the first time tyrosine phosphorylation of p125FAK, p46SHC, and p56SHC in response to angiotensin II. The finding that angiotensin II and platelet-derived growth factor stimulated tyrosine phosphorylation of p46SHC and p56SHC suggested that this protein may serve as a common tyrosine kinase substrate in the mitogenic signaling cascade induced by G-protein-coupled receptors and growth factors and is consistent with the hypothesis that angiotensin II-induced tyrosine phosphorylation is involved in mitogenic signaling pathways in neonatal rat cardiac fibroblasts.
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PMID:Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. 803 31

The potential mechanisms of angiotensin II (ANG II)-induced mitogenesis were studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type 1a ANG II receptor (CHO-AT1a). ANG II had potent mitogenic effects in these CHO-AT1a cells, leading to a sustained increase in cell number as well as a dose-dependent increase in DNA synthesis. ANG II treatment also induced a biphasic elevation of mitogen-activated protein (MAP) kinase activity of both p42MAPK and p44MAPK with a rapid early peak at 5 min (2- to 6-fold) followed by a second sustained increase that reached a peak at 3 h (1.5- to 3-fold). We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonate metabolism plays a key role in ANG II-induced growth of vascular smooth muscle and adrenal cells. In the present study, ANG II (10(-7) M) increased the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE). ANG II-induced DNA synthesis was inhibited by a specific LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10 microM). In contrast, a cyclooxygenase blocker of arachidonate metabolism such as ibuprofen had no effect on ANG II-induced DNA synthesis. ANG II-induced DNA synthesis was also partially (32%) blocked by pertussis toxin (PTX). CDC and PTX also selectively blocked only the late (3 h) peak of ANG II-induced MAP kinase activity, suggesting that the late sustained peak of MAP kinase activity may be linked to the mitogenic effect of ANG II. Direct addition of 12-HETE (10(-7) M) led to a sustained increase in cell number similar to the effect of ANG II. 12-HETE also caused an increase in MAP kinase activity, and 12-HETE effects were blocked by PTX. These results suggest that ANG II-induced mitogenic response is associated with sustained MAP kinase activation and that LO activation may play a key role in this process.
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PMID:Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. 889 27

Rat-1 fibroblasts were transfected with a cDNA encoding the mouse delta opioid receptor. Two separate clones, D2 (which expressed some 6 pmol of the receptor/mg of membrane protein) and DOE (which expressed some 0.2 pmol/mg of membrane protein), were examined in detail. With membranes from both clones, the opioid agonist [D-Ala2]leucine enkephalin (DADLE) caused stimulation of high-affinity GTPase activity and of the binding of guanosine 5'-[gamma-[35S]thio]triphosphate, and inhibition of forskolin-amplified adenylate cyclase activity. DADLE also induced phosphorylation and activation of both the p42MAPK (42 kDa isoform) and p44MAPK (44 kDa isoform) members of the mitogen-activated protein kinase (MAP kinase) family. All of these effects of DADLE were prevented in both clones by pretreatment of the cells with pertussis toxin. The maximal response that could be produced by DADLE in direct assays of G-protein activation were substantially greater in clone D2 than in clone DOE, but in both clones essentially full phosphorylation of both p42MAPK and p44MAPK could be achieved. EC50 values for DADLE stimulation of GTPase activity and for activation of p44MAPK were substantially lower in clone D2 than in clone DOE. Moreover, in both clones the EC50 value for DADLE stimulation of p44MAPK was substantially lower than that for stimulation of GTPase activity, and the Hill coefficients for agonist activation of p44MAPK (h > 1) displayed marked co-operativity whereas those for G-protein activation did not (h 0.8-1.0). DADLE activation of p44MAPK showed more sustained kinetics in clone D2 than in clone DOE. By contrast, lysophosphatidic acid, acting at an endogenously expressed G-protein-coupled receptor, also activated p44MAPK in both clones in a pertussis toxinsensitive manner, but both the kinetics and the concentration-response curve for activation of p44MAPK by this ligand were similar. As with other systems, maintained cellular levels of a cAMP analogue prevented the effects of both G-protein-coupled receptors on activation of p44MAPK. These results demonstrate for the first time that an opioid receptor, at least when expressed in Rat-1 fibroblasts, is able to initiate activation of the MAP kinase cascade in a G1-dependent manner, and show that only a very small proportion of the cellular G1 population is required to be activated to result in full phosphorylation of the p42MAPK and p44MAPK MAP kinases.
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PMID:Agonist activation of p42 and p44 mitogen-activated protein kinases following expression of the mouse delta opioid receptor in Rat-1 fibroblasts: effects of receptor expression levels and comparisons with G-protein activation. 894 92

Rat-1 fibroblasts were used to study the role of the sustained activation of extracellular signal-regulated kinase 1 (ERK1) in lysophosphatidic acid (LPA)-stimulated mitogenic signalling. Mitogenic doses of LPA, like serum, stimulated biphasic, sustained, ERK activation that persisted towards the G1/S boundary. The EC50 for LPA-stimulated ERK activation after 10 min, the time of peak response, was 2 orders of magnitude to the left of that for the sustained response after 3 h or that for DNA synthesis after 22 h, with the result that non-mitogenic doses stimulated a maximal peak response but no second phase. To complement these studies, we examined the role of different signal pathways in regulating the sustained and acute phases of ERK activation using defined biochemical inhibitors and mimetics. Activation of protein kinase C and Ca2+ fluxes played a minor and transient role in regulation of ERK1 activity by LPA in Rat-1 cells. Sustained ERK1 activation stimulated by LPA was completely inhibited by pertussis toxin, whereas the early peak response was only partly affected; this is correlated with the specific inhibition of LPA-stimulated DNA synthesis by pertussis toxin. The selective tyrosine kinase inhibitor herbimycin A completely inhibited sustained ERK1 activation by LPA but, again, the early phase of the response was only partially inhibited. In addition, low doses of staurosporine inhibited ERK1 activation by LPA. The effects of herbimycin A and staurosporine were selective for the response to LPA but did not affect that to epidermal growth factor. The results suggest a strong correlation between sustained ERK1 activation and DNA synthesis in LPA-stimulated Rat-1 cells. Furthermore, the two discrete phases of ERK activation by LPA are regulated by a combination of at least two different signalling pathways; the sustained activation of ERK1 in Rat-1 cells proceeds via a G1- or Gzero-mediated pathway which may also involve a tyrosine kinase.
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PMID:Kinetic and biochemical correlation between sustained p44ERK1 (44 kDa extracellular signal-regulated kinase 1) activation and lysophosphatidic acid-stimulated DNA synthesis in Rat-1 cells. 894 93

The protooncogene G alpha(i-2) plays a pivotal role in signaling pathways that control renal cell growth and differentiation. Mitogen-activated protein kinases (MAPKs) are potential downstream effectors for G alpha(i-2) in these pathways. In predifferentiated LLC-PK1 renal cells, the temporal maximal expression of G alpha(i-2) coincided with maximal activation of MAPK(p42/p44). By contrast, pertussis toxin treatment of these cells inhibited cell growth and reduced MAPK(p42/p44) activity by 30%. These findings reflected upstream activation of MAPK kinase (MEK1), as transient transfection of cells with a plasmid encoding a constitutively active form of MEK1 increased MAPK(p42/p44) activity and cell growth, whereas treatment with PD-098059, an inhibitor of MEK1 activity, reduced MAPK(p42/p44) activity and cell growth. Expression of a guanosinetriphosphatase (GTPase)-deficient G alpha(i-2) in these cells increased MAPK(p42/p44) activity and correspondingly reduced cell doubling time from 24 to 10 h without altering the activity of Raf-1 or c-Jun/stress-activated protein kinases (SAPKs). By contrast, expression of a GTPase-deficient G alpha(i-3) in these cells reduced both their cell doubling time by 30% and MAPK(p42/p44) activity by 60%. As the known MEKK isoforms (MEKK1, -2, and -3) can also activate SAPKs, these findings suggest the GTP-charged G alpha(i-2) subunit transduces growth signals in renal cells via activation of MAPK(p42/p44) and that such activation may be linked to pathways containing novel MEKK isoforms that preferentially activate MEKs.
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PMID:G alpha(i-2) mediates renal LLC-PK1 growth by a Raf-independent activation of p42/p44 MAP kinase. 912 7

Stimulation of Rat-1 cells with lysophosphatidic acid (LPA) or epidermal growth factor (EGF) results in a biphasic, sustained activation of extracellular signal-regulated kinase 1 (ERK1). Pretreatment of Rat-1 cells with either cycloheximide or sodium orthovanadate had little effect on the early peak of ERK1 activity but potentiated the sustained phase. Cycloheximide also potentiated ERK1 activation in Rat-1 cells expressing DeltaRaf-1:ER, an estradiol-regulated form of the oncogenic, human Raf-1. Since cycloheximide did not potentiate MEK activity but abrogated the expression of mitogen-activated protein kinase phosphatase (MKP-1) normally seen in response to EGF and LPA, we speculated that the level of MKP-1 expression may be an important regulator of ERK1 activity in Rat-1 cells. Inhibition of LPA-stimulated MEK and ERK activation with PD98059 and pertussis toxin, a selective inhibitor of Gi-protein-coupled signaling pathways, reduced LPA-stimulated MKP-1 expression by only 50%, suggesting the presence of additional MEK- and ERK-independent pathways for MKP-1 expression. Specific activation of the MEK/ERK pathway by DeltaRaf-1:ER had little or no effect on MKP-1 expression, suggesting that activation of the Raf/MEK/ERK pathway is necessary but not sufficient for MKP-1 expression in Rat-1 cells. Activation of PKC played little part in growth factor-stimulated MKP-1 expression, but LPA- and EGF-induced MKP-1 expression was blocked by buffering [Ca2+]i, leading to a potentiation of the sustained phase of ERK1 activation without potentiating MEK activity. In Rat-1DeltaRaf-1:ER cells, we observed a strong synergy of MKP-1 expression when cells were stimulated with estradiol in the presence of ionomycin, phorbol 12-myristate 13-acetate, or okadaic acid under conditions where these agents did not synergize for ERK activation. These results suggest that activation of the Raf/MEK/ERK pathway is insufficient to induce expression of MKP-1 but instead requires other signals, such as Ca2+, to fully reconstitute the response seen with growth factors. In this way, ERK-dependent and -independent signals may regulate MKP-1 expression, the magnitude of sustained ERK1 activity, and therefore gene expression.
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PMID:Regulation of mitogen-activated protein kinase phosphatase-1 expression by extracellular signal-related kinase-dependent and Ca2+-dependent signal pathways in Rat-1 cells. 914 52

Maximally effective concentrations of the opioid agonist D-ala2-D-leu5-enkephalin resulted in some 2-3-fold enhancement of tyrosine phosphorylation of the p52 Shc adapter protein in a clone of Rat-1 fibroblasts transfected to express stably the murine delta opioid receptor. More limited modifications of the tyrosine phosphorylation status of the p46 and p66 forms of Shc were observed in parallel. Epidermal growth factor caused some 10-12-fold enhancement of tyrosine phosphorylation of p52 Shc and marked increases in the p46 and p66 forms. The effect of D-ala2-D-leu5-enkephalin was prevented by pretreatment of the cells with pertussis toxin and was not observed in non-transfected parental fibroblasts whereas the effect of epidermal growth factor was still manifest in both these situations. Half-maximal effects of D-ala2-D-leu5-enkephalin on p52 Shc tyrosine phosphorylation were produced with sub-nanomolar concentrations, in agreement with previous results on the tyrosine phosphorylation of p44MAPK (Burt et al., 1996). p52 Shc became tyrosine phosphorylated more rapidly than p44MAPK in response to D-ala2-D-leu5-enkephalin and its enhanced tyrosine phosphorylation was maintained for at least 10 min.
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PMID:Agonist-mediated tyrosine phosphorylation of isoforms of the shc adapter protein by the delta opioid receptor. 937 23

The human sst(4) receptor, recombinantly expressed in Chinese hamster ovary cells, mediates proliferative activity of the peptide hormone somatostatin. This effect was shown to involve activation of pertussis toxin-sensitive G proteins and was inhibited by overexpression of the betagamma-sequestrant, transducin. Somatostatin-induced proliferation was abolished by the MEK1 inhibitor, PD 98059, whereas the Src inhibitor, PP1, had no effect. A marked increase was observed in the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) 10 min after sst(4) receptor activation, which was blocked by pertussis toxin, decreased by PP1 and the betagamma-sequestrant, but unaffected by PD 98059. In contrast, the somatostatin-induced phosphorylation of ERK obtained at 4 h, although sensitive to both pertussis toxin and transducin, was unaffected by PP1 but ablated by PD 98059. Protein kinase C inhibition also abolished this somatostatin-induced sustained phosphorylation of ERK, together with the associated increase in cell proliferation. Expression of dominant negative Ras (N17) failed to significantly reduce the proliferative effect mediated by the sst(4) receptor but markedly attenuated the acute phase of the somatostatin-induced phosphorylation of ERK obtained at 10 min. In contrast, the phosphorylation induced at 4 h was unaffected. We conclude that ERK activation by G(i/o)-coupled sst(4) receptors involves a Src and Ras-dependent acute phase, but the proliferative response is dependent upon the prolonged ERK-induced activity, mediated by protein kinase C.
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PMID:Prolonged activation of extracellular signal-regulated kinase by a protein kinase C-dependent and N17Ras-insensitive mechanism mediates the proliferative response of G(i/o)-coupled somatostatin sst(4) receptors. 1044 4

Many G protein-coupled receptor agonists activate p42/p44 mitogen-activated protein kinase (MAPK), using signaling pathways that are a function of receptor, G protein-coupled, and effector complement. In opossum kidney (OK) cells, activation of endogenous PTH receptors caused a time- (peak within 15-30 min, sustained for approximately 2 h) and dose-dependent (EC50 approximately 3 x 10(-10) M) activation of MAPK. Immunoblot analysis with an activation- specific MAPK antibody indicated that PTH activated both p42 and p44 MAPK. Epidermal growth factor (EGF) also activated p42 and p44MAPK in a time- (peak at 5 min, return to basal within 2 h) and dose-dependent (EC50 approximately 3 ng/ml) fashion. PTH-dependent MAPK activation was mimicked by the protein kinase C activator (PKC) phorbol myristate acetate (PMA), and the protein kinase A activators 8 bromo-cAMP (8-Br-cAMP) and forskolin but was not affected by pertussis toxin pretreatment. PMA or 8-Br-cAMP pretreatment blocked MAPK activation by reexposure to each kinase activator but caused no significant reduction in MAPK activation by PTH. MAPK activation by PTH, EGF, and 8-Br-cAMP was inhibited by the MAPK kinase inhibitor PD98059 and an EGF receptor (EGFR)-selective inhibitor tyrphostin AG1478. AG1478 also blocked MAPK activation by insulin-like growth factor-1 and platelet-derived growth factor. EGF and PTH caused time- and AG1478-sensitive phosphorylation of the EGFR, but EGFR desensitization did not affect MAPK activation by PTH. EGF, PMA, and low doses of PTH (10(12) to 10(-9) M) stimulated while 8-Br-cAMP and high doses of PTH (10(-8) to 10(-6) M) inhibited [3H]thymidine uptake. These data demonstrate that PTH activates MAPK and suggest that PKC, protein kinase A, and the EGFR play roles in PTH signaling. The biphasic effect of PTH on DNA synthesis suggests that MAPK activation by the hormone leads to distinct cellular responses.
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PMID:Parathyroid hormone activates mitogen-activated protein kinase in opossum kidney cells. 1057 43

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