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)

Treatment of human vascular smooth muscle cells (SMC) with human alpha-thrombin greatly increased DNA synthesis and cell proliferation. Both the integrity of the catalytic site and that of the anion binding exosite were required for expression of this activity. Experiments employing Northerns indicated induction of c-fos expression as well as a time-dependent induction of platelet-derived growth factor-A (PDGF-A) gene by thrombin. The thrombin mitogenic activity was potentiated by PDGF-BB, insulin and the vasoconstrictor peptide endothelin-1 suggesting synergism by convergence of intracellular growth-promoting signals. SMC treatment with pertussis toxin and forskolin indicated that the mitogenic activity of thrombin may be induced via signal transduction mechanism(s) involving changes in cAMP levels and activation of a Gi-like protein. These results suggest that thrombin may play a functional role in the regulation of human vascular SMC proliferation.
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PMID:Thrombin-induced proliferation and expression of platelet-derived growth factor-A chain gene in human vascular smooth muscle cells. 133 90

The mitogenic effect of extracellular ATP on porcine aortic smooth muscle cells (SMC) was examined. Stimulation of [3H]thymidine incorporation by ATP was dose-dependent; the maximal effect was obtained at 100 microM. ATP acted synergistically with insulin, IGF-1, EGF, PDGF, and various other mitogens. Incorporation of [3H]thymidine was correlated with the fraction of [3H]thymidine-labeled nuclei and changes in cell counts. The stimulation of proliferation was also determined by measurement of cellular DNA using bisbenzamide and by following the increase of mitochondrial dehydrogenase protein. The effect of ATP was not due to hydrolysis to adenosine, which shows synergism with ATP. ATP acted as a competence factor. The mitogenic effect of ATP, but not adenosine, was further increased by lysophosphatidate, phosphatidic acid, or norepinephrine. The inhibitor of adenosine deaminase, EHNA, stimulated the effect of adenosine but not ATP. The adenosine receptor antagonist theophylline depressed adenosine-induced mitogenesis. ADP and the non-hydrolyzable analogue adenosine 5'-[beta, gamma-imido]triphosphate (AMP-PNP) were equally mitogenic. Thus extracellular ATP stimulated mitogenesis of SMC via P2Y purinoceptors. The mechanism of ATP acting as a mitogen in SMC was further explored. Extracellular ATP stimulated the release of [3H]arachidonic acid (AA) and prostaglandin E2 (PGE2) into the medium, and enhanced cAMP accumulation in a dose-dependent fashion similar to ATP-induced [3H]thymidine incorporation. Inhibitors of the arachidonic acid metabolism pathway, quinacrine and indomethacin, partially inhibited the mitogenic effect of ATP but not of adenosine. Pertussis toxin inhibited ATP-stimulated DNA synthesis, AA release, PGE2 formation, and cAMP accumulation. Down-regulation of protein kinase C (PKC) by long-term exposure to phorbol dibutyrate (PDBu) partially prevented stimulation of DNA synthesis and activation of the AA pathway by ATP. The PKC inhibitor, staurosporine, antagonized mitogenesis stimulated by ATP. No synergistic effect was found when PDBu and ATP were added together. Therefore, a dual mechanism, including both arachidonic acid metabolism and PKC, is involved in ATP-mediated mitogenesis in SMC. In addition, ATP acted synergistically with angiotensin II, phospholipase C, serotonin, or carbachol to stimulate DNA synthesis. Finally, the possible physiological significance of ATP as a mitogen in SMC was further studied. The effect of endothelin and heparin, which are released from endothelial cells, on ATP-dependent mitogenesis was investigated. Extracellular ATP acted synergistically with endothelin to stimulate a greater extent of [3H]thymidine incorporation than was seen with PDGF plus endothelin. Heparin, believed to have a regulatory role, partially inhibited the stimulation of DNA synthesis caused both by ATP and PDGF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Extracellular ATP and ADP stimulate proliferation of porcine aortic smooth muscle cells. 135 98

The mechanisms of growth factor action were studied in a fibroblastic cell line capable of reversible growth arrest in G0-G1. This cell line, derived from Chinese hamster lung, can be stimulated to divide by a limited set of purified growth factors, including EGF, FGF, PDGF, alpha-thrombin (THR), serotonin (5-HT) and insulin. THR and 5-HT stimulate, via a G-protein (Gp), a polyphosphoinositide-specific phospholipase C (PtdIns(4,5)P2-PLC). In contrast, the mitogens EGF, FGF, PDGF, and insulin do not stimulate PtdIns(4,5)P2-PLC unless this pathway has been preactivated by THR or AlF-4. Finally, from the specific inhibitory action of pertussis toxin on THR- and 5-HT-induced DNA synthesis, and from the exploitation of the 5-HT pharmacological tools, we conclude that: (i) there are at least two distinct G-proteins involved in signalling growth: Gp, coupling receptors to PtdIns(4,5)P2-PLC, and Gi, coupling receptors negatively to adenylyl cyclase and probably to other unknown effector(s); (ii) activation of receptor-tyrosine kinases provides an alternate growth factor signalling pathway, independent of Gp- and Gi-mediated actions; and (iii) tyrosine kinases positively 'cross-communicate' with the inositol-lipid pathway (phosphorylation of Gp, PLC, PtdIns kinases...?).
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PMID:Transmembrane signalling pathways initiating cell growth in fibroblasts. 290 48

Mast cells accumulate at sites of angiogenesis. The factor(s) that control mast-cell recruitment at these sites have yet to be defined. We sought to determine if angiogenic factors result in mast-cell chemotaxis. In this study, we observed that platelet-derived growth factor-AB (PDGF-AB), vascular endothelial cell growth factor (VEGF), and basic fibroblast growth factor (bFGF) each cause directed migration of murine mast cells at picomolar concentrations, with a typical bell-shaped dose-response curve. Another potent angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), appears to promote chemokinesis of mast cells, whereas tumor necrosis factor-alpha, a weak angiogenic factor, is less robust but still functions as a mast cell chemotactic factor. Epidermal growth factor (EGF), a growth factor with minimal angiogenic properties, was ineffective as a mast cell chemotactic factor. A checkerboard analysis confirmed the directional chemotactic response of PDGF-AB, VEGF, and bFGF, while indicating the chemokinetic response induced by PD-ECGF. Cross-desensitization of growth-factor-induced directed migration was observed between PDGF-AB and bFGF, and also between PDGF-AB and PD-ECGF. Tyrosine kinase-inhibitor genistein effectively dampened the chemotactic responses, whereas pertussis toxin had no effect. In summary, our findings suggest that factors known to act on endothelial cells and stimulate neovascularization may simultaneously serve to recruit mast cells to these sites. The local accumulation of mast cells is believed to facilitate new vessel formation through complex cell:cell interactions.
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PMID:Angiogenic factors stimulate mast-cell migration. 754 57

Ras-GRF, a guanine-nucleotide exchange factor that activates Ras p21, was tested for its ability to couple to either tyrosine kinase or heterotrimeric G protein signal transduction pathways. Ras-GRF failed to bind the SH2 and SH3 containing adaptor protein Grb2, either in vitro or in vivo. Furthermore, Ras-GRF did not form a stable complex with activated EGF receptor. However, as has been shown previously (Cen et al., 1994), the presence of Ras-GRF in NIH3T3 cells enhanced the activation of Ras induced by serum stimulation. A similar effect was not observed with PDGF stimulation. Moreover, serum stimulation lead to the hyperphosphorylation of Ras-GRF. Both the serum induced super-activation of Ras, and the hyperphosphorylation of Ras-GRF were blocked by pretreatment of cells with the Gi,o inhibitor pertussis toxin, but not by pretreatment with the tyrosine kinase inhibitor genistein. These results suggest that Ras-GRF has the capacity to mediate Ras activation initiated by signals using heterotrimeric G proteins.
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PMID:Differential response of the Ras exchange factor, Ras-GRF to tyrosine kinase and G protein mediated signals. 776 Oct 90

In pulmonary vascular remodelling, the lining smooth muscle cells undergo various forms of growth involving cellular hypertrophy and hyperplasia. Differences in the growth pattern between central and peripheral regions suggested that cells from both should be obtained when investigating the cellular basis for the remodelling. Accordingly, we have obtained two smooth muscle cell types in culture: a cell from the central pulmonary artery (CC) and a cell morphologically similar to a pericyte (PC), from the periphery of the lung. Both cell types gave positive immunostaining for alpha-smooth muscle isoactin. In vivo, the alpha-isoactin was immunolocalized in the extracapillary vasculature. Quantitative two-dimensional gel electrophoresis of cell extracts showed that PC express more vimentin and gelsolin than CC. Despite the differences between PC and CC in the expression of cytoskeletal proteins, their response to growth factors was similar. Both cell types increased DNA synthesis when stimulated by exogenous PDGF-AB. This occurred in the absence of exogenous progression factors, but depended on a post-competence, suramin-sensitive mechanism that probably represents an autocrine progression factor. The cells were also stimulated by IGF-1 alone, in the absence of exogenous competence factors. At an IGF-1 concentration of 1 ng/ml, this response appeared specific for the IGF-1 receptor and was sensitive to pretreatment with pertussis toxin, thus implicating a role for a G protein.
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PMID:Peripheral and central vascular smooth muscle cells from rat lung exhibit different cytoskeletal protein profiles but similar growth factor requirements. 818 57

Cementum-derived growth factor (CGF) is a M(r) 23,000 protein, which is sequestered in the mineralized matrix of tooth cementum. We have investigated the mitogenic signaling reactions induced by CGF using quiescent human gingival fibroblasts as target cells. Cells activated with CGF were compared with those treated with CGF plus epidermal growth factor (EGF) and other growth factors. CGF caused a transient increase in cytoplasmic Ca2+ concentration, and this was accompanied by enhancement of membrane protein kinase C activity, myelin basic protein and S6 kinase activities, inositol phosphate levels, and activation of c-fos and jun-B gene expression. Membranes obtained from cells activated with CGF contained several protein bands, which cross-reacted with antiphosphotyrosine antibody; however, proteins corresponding to a putative phosphorylated CGF receptor were not detected. DNA synthesis induced by CGF was inhibited by 65% in cells treated with pertussis toxin but only 25-29% in cultures exposed to H7 or 12-O-tetradecanoylphorbol-13-acetate; these values were different from those obtained when EGF, PDGF, or fetal bovine serum were used as mitogens. CGF and TGF-beta, but not EGF, caused an increase of PDGF-A chain mRNA expression 4 h after mitogen addition. However, while CGF was mitogenic for gingival fibroblasts, TGF-beta was not. Kinetics of DNA stimulation and experiments with anti-PDGF antibodies indicated that PDGF-A expression does not contribute significantly to CGF-induced DNA synthesis. When the stimulation of various signaling pathways induced by CGF and other growth factors was compared, the pattern of stimulation by CGF was different from other growth factors. The characteristic signaling reactions of CGF are likely to be important components of the mechanisms that regulate the formation and regeneration of cementum and adjacent connective tissues.
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PMID:Mitogenic signaling mechanisms of human cementum-derived growth factors. 825 29

The synthetic peptide SFLLRNPNDKYEPF, identical in sequence to the new amino-terminus of the thrombin receptor generated following cleavage of thrombin, acts a thrombin receptor agonist/activating peptide (TRAP). In this study, Northern blot analysis showed that cultured human vascular smooth muscle cells (HVSMC) express a thrombin receptor transcript. TRAP, in contrast to thrombin was shown to be a weak mitogen for HVSMC. A combination of TRAP and enzymatically-inactivated thrombin (PPACK-thrombin) which provides receptor occupancy, did not potentiate TRAP-induced mitogenesis, indicating that TRAP and PPACK-thrombin do not reproduce the mitogenic effect of enzymatically-active thrombin. Both thrombin and TRAP, induced the expression of c-fos and the PDGF-A gene in a pertussis toxin (PTX)-insensitive manner. Examination of thrombin and TRAP-treated cells by immunofluorescence staining followed by computer assisted image analysis revealed that thrombin and to a lesser extent TRAP induced PDGF-AA protein expression. Antibodies to PDGF-AA partially inhibited thrombin but not TRAP-induced mitogenesis in HVSMC. This study indicates that in addition to the common signalling pathways utilised by thrombin and TRAP, enzymatically-active thrombin activates other signalling pathways and hence TRAP does not mimic fully the biological effect of thrombin on HVSMC.
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PMID:Thrombin receptor activating peptide (TRAP) stimulates mitogenesis, c-fos and PDGF-A gene expression in human vascular smooth muscle cells. 860 20

We investigated the signaling pathways mediating 1-pS Ca2+ channel activation by PDGF in cultured rat mesangial cells. In cell-attached patches, intrapipette PDGF-BB (PDGF B chain homodimer isoform) (50 ng/ml) dramatically stimulates channel activity (P < 0.003, n = 6). Tyrosine kinase inhibition (100 microM genistein or 10 microM tryphostin 9) abolished PDGF-induced channel activation (P < 0.02, n = 6). In excised patches, the effect of tyrosine kinase inhibition could be reversed by 200 microM GTPgammaS (P < 0.02, n = 4). In contrast, 200 microM GDPbetaS inhibited PDGF-induced channel activity (P < 0.04, n = 6). Pertussis toxin (250 ng/ml) had no effect on PDGF-induced channel activity (P = 0.45, n = 6). When excised patches were exposed to anti-Ras antibody (5 microg/ml), PDGF-induced channel activity was abolished (P < 0.002, n = 11). Western immunoblots revealed that PDGF-BB binding stimulates the formation of a membrane-bound complex consisting of growth factor receptor-binding protein 2, son of sevenless, and the PDGF-beta receptor. Complex formation was abolished by genistein. In mesangial cells, the intrinsic tyrosine kinase activity of the PDGF-beta receptor stimulates the formation of a membrane-bound growth factor receptor-binding protein 2/son of sevenless/PDGF-beta receptor complex and activation of the pertussis toxin-insensitive GTP-binding protein, p21-Ras, which leads to the opening of 1-pS Ca2+ channels.
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PMID:Ca2+ channel activation by platelet-derived growth factor-induced tyrosine phosphorylation and Ras guanine triphosphate-binding proteins in rat glomerular mesangial cells. 863 14

CDC25Mm is a mouse guanine nucleotide exchange factor specific for Ras, exclusively expressed in the brain. We used a reporter gene containing a Ras-responsive fos-promoter in order to gain information on the role played by this exchange factor in signal transduction. Transient expression of CDC25Mm in CHO cells activates Ras. Moreover serum, but not insulin, can upregulate the response mediated by CDC25Mm and this modulation requires that the CDC25Mm maintains its N-terminal region. NIH3T3 fibroblasts, stably overexpressing this exchange factor, show a partially transformed phenotype, suggesting that the Ras-dependent pathway is constitutively active. In these cells serum and lysophosphatidic acid (LPA) stimulate Ras activity above the basal level while PDGF does not. Both serum and LPA-induced Ras activations in CDC25Mm overexpressing cells can be completely inhibited by pertussis toxin. Moreover, these responses are strongly reduced by coexpression of a truncated version of CDC25Mm lacking the C-terminal catalytic portion. This construct behaves in a dominant negative manner suggesting that it may compete with CDC25Mm by sequestering in an unproductive way signalling components activated by these factors. The data presented indicate that CDC25Mm does not participate in connecting tyrosine kinase receptors with Ras, while it could mediate Ras activation induced by pertussis toxin sensitive Gi-coupled receptors.
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PMID:The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals. 870 May 29


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