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)

Since in 1986 it was reported that a pertussis toxin-sensitive substrate was involved in the Ca2+ signal induced by epidermal growth factor (EGF) in rat hepatocytes, much evidence accumulated to implicate heterotrimeric G-proteins in EGF action. EGF can also induce a cyclic AMP signal, but while the generation of a Ca2+ signal appears to be quite general in EGF action, the increase in cyclic AMP occurs only in few cell types. In non-transformed cell types these effects appear to involve G-proteins. EGF not only induces cell proliferation but also interacts with hormones in the short-term control of cell function in quiescent cells. Most of the known interactions are on cyclic AMP mediated hormone effects, and in many cases, the interaction between EGF and hormones involves G-proteins. Here we review the evidence accumulated in recent years that implicate G-proteins in EGF action. An understanding of the mechanisms involved may reveal new mechanisms of G-protein regulation and will contribute to our knowledge of EGF function and signal transduction.
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PMID:Role of heterotrimeric G-proteins in epidermal growth factor signalling. 852 98

Ethanol modulates agonist responses in liver cells, which are the major site of ethanol metabolism. Mitogen-activated protein kinases (MAPKs) are involved in the integration of multiple signaling pathways leading to cellular responses. However, the effect of ethanol on liver MAPK is not known. To this end, we studied the activation of MAPK in a normal mouse embryonic liver cell line (BNLCL2) after acute and chronic exposure to ethanol. Acute exposure to ethanol (0-400 mM) for 1 hr had no effect on either basal or serum- and phorbol-12-myristate-13-acetate (PMA)-stimulated MAPK activity. Chronic exposure to ethanol (0-400 mM) for 24 hr potentiated the stimulation of MAPK by serum, PMA, or thrombin. Maximum potentiation was observed with 200 mM ethanol (2- to 3-fold higher than control cells). Chronic exposure had no significant effect on epidermal growth factor-stimulated MAPK activity. In-gel MAPK assay of cytosolic extracts and of immunoprecipitates obtained with MAPK antibody demonstrated that ethanol potentiated the activation of both p42 and p44 MAPKs. When cells were pretreated with pertussis toxin, the potentiation by ethanol was abolished. It is concluded that ethanol potentiates MAPK in fetal liver cells by a pertussis toxin-sensitive G-protein-dependent mechanism.
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PMID:Potentiation of mitogen-activated protein kinase by ethanol in embryonic liver cells. 861 3

Increased intracellular cyclic adenosine monophosphate (cAMP) levels have been shown in some reports to inhibit and in other studies to stimulate growth factor-mediated activation of the mitogen-activated protein kinase (MAP kinase) pathway, depending on the cell type examined. The relationship between cAMP and MAP kinase in hepatocytes has not been examined. In the current study, stimulation of primary cultures of rat hepatocytes with hepatocyte growth factor (HGF) or epidermal growth factor (EGF) increased Ras, Raf, and MAP kinase activity. Incubation of hepatocytes with cAMP-increasing agents blocked activation of Raf by both HGF and EGF, whereas activation of Ras was unaffected. MAP kinase activation by HGF was completely inhibited, whereas EGF-stimulated MAP kinase activity was only slightly reduced. Incubation of hepatocytes with pertussis toxin slightly blunted MAP kinase activation by EGF but not HGF. Increasing cAMP in hepatocytes preincubated with pertussis toxin completely inhibited the activation of MAP kinase by EGF. In conclusion, HGF activates MAP kinase in hepatocytes exclusively through an Raf-dependent pathway and this activation may be completely blocked by increasing cAMP. In contrast, EGF activates MAP kinase in hepatocytes through both Raf-dependent and Raf-independent pathways: the latter pathway probably involves a pertussis toxin-sensitive G protein.
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PMID:Inhibitory actions of cyclic adenosine monophosphate and pertussis toxin define two distinct epidermal growth factor-regulated pathways leading to activation of mitogen-activated protein kinase in rat hepatocytes. 862 Nov 50

Tumor necrosis factor (TNF) activates both p42 and p44 mitogen-activated protein kinases (MAPK) in human FS-4 fibroblasts, cells for which TNF is mitogenic. We now show that TNF activates p42 MAPK in two cell lines whose growth is inhibited by TNF. A mutant TNF that binds only to the p55 TNF receptor (TNFR) produced a similar degree of activation as wild-type TNF in FS-4 fibroblasts, indicating that the p55 TNFR is sufficient to mediate p42/p44 MAPK activation. The upstream intracellular signals that couple the TNFR to MAPK activation are still poorly defined. We now show that neither phorbol ester-sensitive protein kinase C nor Gialpha link TNF to p42/p44 MAPK activation, because pretreatment of FS-4 cells with phorbol ester to down-regulate protein kinase C or pretreatment with pertussis toxin to block Gialpha does not inhibit p42/p44 MAPK activation by TNF. To further analyze MAPK activation in FS-4 cells, we compared p42/p44 MAPK activation by TNF and epidermal growth factor (EGF). While tyrosine phosphorylation of p42/p44 MAPK was detected almost immediately (30 s) after stimulating cells with EGF, TNF-induced tyrosine phosphorylation was detected only after a more prolonged time interval (initially detected at 5 min and peaking at 15-30 min). In addition, the anti-inflammatory drug sodium salicylate, previously demonstrated to inhibit NF- kappaB activation by TNF, blocked the activation of p42/p44 MAPK in response to TNF but not in response to EGF. These findings demonstrate that the TNF and EGF receptors utilize distinct signaling molecules to couple to MAPK activation. Elucidation of the mechanism whereby sodium salicylate blocks TNF-induced p42/p44 MAPK activation may help to clarify TNF-activated signaling pathways.
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PMID:Inhibition of tumor necrosis factor-induced p42/p44 mitogen-activated protein kinase activation by sodium salicylate. 862 94

The effects of epidermal growth factor (EGF) and cell density on the appearance of beta-adrenergic responses were examined in primary cultures of adult rat hepatocytes. The beta-adrenergic response was measured as the ability to accumulate cAMP by beta 2-agonist metaproterenol in monolayers that had been cultured without or with 20 ng/ml EGF. Hepatocytes cultured with EGF at a high cell density (1.0 x 10(5) cells/cm2) showed a relatively lower response to 10 microM metaproterenol. In contrast, when cultured at a low cell density (3.3 x 10(4) cells/cm2) with EGF, the cells showed a higher response to the beta-adrenergic agonist. These responses were blocked by the beta-adrenergic antagonist propranolol (10 microM). The beta-adrenergic response increased rapidly with culture time. The addition of cycloheximide (5 microM) to the culture abolished the expression of beta-adrenergic response. The enhanced beta-adrenergic response by 20 ng/ml EGF was partially inhibited by the addition of cytochalasin B (20 microM) to the culture. The cAMP-producing response to metaproterenol (10 microM) was dose-dependently inhibited by the specific x2-agonist UK-14304. Pretreatment of the hepatocytes with pertussis toxin (100 ng/ml) potentiated the beta-adrenergic response. These results demonstrate that augmented beta-adrenergic responsiveness can be acquired by adult rat hepatocytes cultured with 20 ng/ml EGF at a low cell density, and the beta-adrenergic response involves de novo synthesis of protein(s). The results also show that significant alpha 2- and beta-adrenergic responses coexist in the primary cultures of adult rat hepatocytes.
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PMID:Cell-density-dependent expression of the beta-adrenergic response by epidermal growth factor (EGF) in primary cultures of adult rat hepatocytes. 874 89

Angiotensin II (ANG II), a potent growth-promoting factor of vascular smooth muscle cells (VSMC), induces activation of mitogen-activated protein (MAP) kinases and subsequent expression of the c-fos protooncogene in VSMC. However, it remains obscure whether ANG II induces activation of the ras protooncogene product (Ras), and if it does, whether Ras is involved in signaling from the ANG II receptor to the MAP kinase pathway in VSMC. In cultured VSMC, ANG II activated Ras comparably to epidermal growth factor. ANG II-induced Ras activation was detectable within 1 min and maximal at 2-5 min. The ANG II type 1 (AT1) receptor antagonist, CV-11974, completely inhibited this reaction. Pertussis toxin treatment of VSMC inhibited ANG II-induced Ras activation by approximately 70% but had no effect on ANG II-induced MAP kinase activation and c-fos expression. These results indicate that ANG II activates Ras via AT1 receptors, which are predominantly linked to a G protein of the Gi subfamily in VSMC1 and suggest that Ras activation may not be a prerequisite for ANG II-induced MAP kinase activation and c-fos expression in this cell type.
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PMID:Angiotensin II type 1 receptor-mediated activation of Ras in cultured rat vascular smooth muscle cells. 877 Jan 1

Long chain saturated fatty acids are known to inhibit breast cancer cell proliferation; however, the mechanism of this inhibition is not known. Treatment of Hs578T breast cancer cells with long chain saturated fatty acids (0.15 mmol/L for 6 hours) before epidermal growth factor (EGF) treatment inhibited EGF-induced cell proliferation in a chain-length-dependent manner. Stearate (C:18) completely inhibited the EGF-induced cell proliferation, whereas palmitate (C:16) inhibited by 67 +/- 8% and myristate (C:14) had no effect. In contrast, stearate had little effect on insulin-like growth factor-1-stimulated cell proliferation. The inhibitory effect of stearate on cell proliferation was dose and time dependent and independent of EGF receptor (EGFR) tyrosine phosphorylation. Pretreatment of cells with pertussis toxin (0.1 microgram/ml for 24 hours) inhibited the EGF-induced cell growth by 50 +/- 8%, also independent of EGFR tyrosine phosphorylation. A pertussis-toxin-sensitive, 41-kd G-protein was specifically co-immunoprecipitated with the EGFR. Pretreatment of cells with 0.15 mmol/L stearate from 0 to 6 hours inhibits, in parallel, both the EGF-induced cell proliferation and pertussis-toxin-catalyzed ADP ribosylation of the G-protein associated with the EGFR. These studies suggest that long chain saturated fatty acids inhibit EGF-induced breast cancer cell growth via a mechanism involving an EGFR-G-protein signaling pathway.
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PMID:Stearate inhibition of breast cancer cell proliferation. A mechanism involving epidermal growth factor receptor and G-proteins. 877 53

Effects of epidermal growth factor (EGF) on the expression of alpha(2)-adrenergic responses were examined in primary cultures of adult rat hepatocytes. The alpha(2)-responses were assessed by the inhibition of the rate of forskolin-stimulated cAMP formation by the selective alpha(2)-adrenergic agonists, oxymetazoline and UK-14304. Hepatocytes cultured with EGF (20 ng/ml) at a high cell density (1.0 x 10(5)/cm2) showed almost no response to the alpha(2)-adrenergic agonists, oxymetazoline and UK-14304 (1-100 mu M). In contrast, when cultured at a low cell density (3.3 x 10(4) cells/cm2) with EGF, forskolin-stimulated cAMP production was inhibited by oxymetazoline and UK-14304 in a dose-dependent manner. The alpha(2)-response was blocked by the alpha2-antagonist yohimbine (10 mu M). It was also reversed by treatment of hepatocytes with pertussis toxin (100 ng/ml). In addition, the effects of EGF on the appearance of alpha(2)-responses were almost completely inhibited by treatment of the hepatocytes with genistein (10 mu M) or cytochalasin B (10 mu M). The alpha(2)-response was abolished when cycloheximide (5 mu M) was added to the cultures. These results demonstrate that when cultured at a low cell density with EGF, adult rat hepatocytes acquire a significant alpha(2)-adrenergic response. The expression of this alpha(2)-response is associated with de novo protein synthesis.
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PMID:Cell-density-dependent expression of the alpha(2)-adrenergic response by epidermal growth factor (EGF) in primary cultures of adult rat hepatocytes. 886 Sep 50

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 objective of this study was to investigate the mechanism of action of PGF2 alpha in cultured human myometrial cells. We measured the effects of PGF2 alpha and fluprostenol, a selective PGF2 alpha receptor (FP receptor) agonist, on phospholipase C(PLC) activation, on changes in the intracellular free calcium concentration ([Ca2+]i), and on protein tyrosine phosphorylation. PGF2 alpha and fluprostenol activated PLC (determined by measuring the formation of inositol phosphates) and increased [Ca2+]i in a concentration-dependent manner. The apparent affinity of the FP receptor for fluprostenol was higher than that for PGF2 alpha when measuring PLC activation, but the receptor displayed similar affinities for both agonists when measuring increases in [Ca2+]i. These effects were not altered by treating the cells with pertussis toxin (PT), suggesting that the FP receptor is linked to PLC activation by a G protein of the Gq family. By contrast, the effect of oxytocin on PLC activation involved both PT-resistant and PT-sensitive pathways. Human myometrial cells responded to pervanadate and epidermal growth factor with increased PLC activity and increased tyrosine phosphorylation, demonstrating a functional PLC-gamma tyrosine kinase pathway. However, neither fluprostenol nor oxytocin stimulated tyrosine phosphorylation, but the effects of both agonists were inhibited after protein kinase C stimulation. These data suggest that fluprostenol and oxytocin activate PLC-beta rather than PLC-gamma isoforms. The effect of fluprostenol is Ca2+ dependent, but is unlikely to involve a direct effect of Ca2+ on PLC activity.
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PMID:Fluprostenol activates phospholipase C and Ca2+ mobilization in human myometrial cells. 896 35


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