Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Chronic incubation of cultured renal tubular epithelial cells in acid medium causes an increase in Na/H antiporter activity that persists after removal from acid, is dependent on protein synthesis, and is associated with an increase in Na/H antiporter mRNA. Chronic activation of protein kinase C has similar effects in these cells. The present studies examined the role of protein kinase C in the effect of acid incubation. Incubation of MCT cells in acid for 24 h caused a 50% increase in Na/H antiporter activity. This was prevented by inhibition of protein kinase C, either with sphingosine or by protein kinase C downregulation. Pertussis toxin pretreatment did not prevent the increase in antiporter activity. Acid incubation caused an increase in transcription factor AP-1 activity, as shown by an increase in expression from a reporter gene containing six tandem AP-1 binding sites. This was associated with transient increases in c-fos and c-jun mRNAs. This response is typical of that for gene activation by protein kinase C. These studies demonstrate that acid activation of the Na/H antiporter requires protein kinase C and is associated with c-fos and c-jun expression and increased AP-1 activity.
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PMID:Role of protein kinase C and transcription factor AP-1 in the acid-induced increase in Na/H antiporter activity. 131 56

We have reported previously that the widespread inhibitory actions of somatostatin might be mediated by its ability to inhibit the expression of the immediate early genes c-fos and c-jun. The products of these genes form a heterodimeric transcription factor complex [activator protein 1 (AP-1)], which is known to be induced by treatment with phorbol esters. In the present study, we sought to investigate the mechanisms by which somatostatin inhibits immediate early gene expression. For our experiments, we used a rat pituitary adenoma cell line (GH3), which is known to express multiple subclasses of somatostatin receptors. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated both AP-1 binding and transcriptional activity in GH3 cells and the somatostatin analogue octreotide inhibited this response by 40-70%. In the presence of two different phosphatase inhibitors, sodium orthovanadate or okadaic acid, the ability of somatostatin to inhibit AP-1 binding and transcriptional activity was abolished. This effect of octreotide, which appears to be mediated by the SSTR2 and SSTR5 subtypes of somatostatin receptors, was paralleled by its ability to inhibit TPA-stimulated GH3 cell proliferation. Pretreatment of the GH3 cells with pertussis toxin (200 ng/ml) reversed the inhibitory effect of octreotide on both AP-1 function and cellular proliferation. Our observations lead us to conclude that somatostatin not only inhibits immediate early gene expression but also inhibits AP-1 binding and transcriptional activity via the action of several classes of protein phosphatases. This effect, which is pertussis toxin sensitive, might be one mechanism by which somatostatin inhibits cellular proliferation.
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PMID:Somatostatin inhibits AP-1 function via multiple protein phosphatases. 763 95

Thrombin stimulation of 1321N1 astrocytoma cells leads to Ras-dependent AP-1-mediated transcriptional activation and to DNA replication. In contrast to what has been observed in most cell systems, in 1321N1 cells these responses are pertussis toxin-insensitive. The pertussis toxin-insensitive G-protein G12 has been implicated in cell growth and transformation in different cell systems. We have examined the potential role of this protein in AP-1-mediated transcriptional activation and DNA synthesis in 1321N1 cells. Transient expression of an activated (GTPase-deficient) mutant of G alpha 12 increased AP-1-dependent gene expression. This response was inhibited by co-expression of a dominant negative Ala-15 Ras protein. To determine whether the pertussis toxin-insensitive G12 protein is involved in the thrombin-stimulated DNA synthesis, an inhibitory antibody against the C-terminal sequence of G alpha 12 subunit was microinjected into 1321N1 cells. Microinjection of the anti-G alpha 12 resulted in a concentration-dependent inhibition of thrombin-stimulated DNA synthesis. In contrast, microinjection of nonimmune IgG or an antibody directed against the C terminus of G alpha o did not reduce the mitogenic response to thrombin. Furthermore, microinjection of the anti-G alpha 12 antibody had no effect on fibroblast growth factor-stimulated DNA synthesis. These results demonstrate a specific role for G alpha 12 in the mitogenic response to thrombin in human astroglial cells.
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PMID:G12 requirement for thrombin-stimulated gene expression and DNA synthesis in 1321N1 astrocytoma cells. 765 24

Endothelin (ET) peptides are potent growth factors that bind to G protein-coupled receptors. Although short-term signals activated by ET receptors have been extensively characterized, relatively little is known about mitogenic signal transduction. We investigated the ET receptor subtype involved in mitogenic signaling in glomerular mesangial cells and the role of protein kinase C (PKC) and protein tyrosine kinase (PTK) activity. Pertussis toxin attenuates increases in [Ca2+]i by ET-1 but not [3H]thymidine uptake. An ETA-selective receptor antagonist, BQ 123, blocks increments in [Ca2+]i by ET-1 and inhibits [3H]thymidine uptake. A nonselective ETA-ETB receptor antagonist (PD 142893) blocked [3H]thymidine uptake, but ETB receptor-selective agonists (S6c and [Ala1,Ala3,Ala11,Ala15]ET-1(6-21)) were unable to increase [Ca2+]i or [3H]thymidine uptake. Collectively, these data suggest that mitogenic signaling occurs through an ETA receptor subtype in mesangial cells. Experiments with both PKC inhibition and depletion demonstrate that PKC was necessary but not sufficient for mitogenic signaling. ET-1 increased tyrosine phosphorylation of cellular proteins in quiescent mesangial cells that was blocked by preincubation with herbimycin A. Two chemically and mechanistically dissimilar PTK inhibitors (herbimycin A and genistein) blocked [3H]thymidine uptake by ET-1. In addition, herbimycin A attenuated c-fos induction, AP-1 DNA binding, and transcription directed by an AP-1 cis-element in response to ET-1. Taken together, these data suggest that mitogenic signaling by ET-1 also involves a PTK-based mechanism. We further demonstrated that ET-1 stimulated autophosphorylation of pp60c-src and pp60c-src-catalyzed phosphorylation of a peptide substrate specific for PTK activity. That the dose-response relationship for ET-1-induced pp60c-src activation and [3H]thymidine uptake were similar suggests that these events might be functionally linked. Thus, cross-talk between G protein-coupled receptors and nonreceptor PTK such as pp60c-src might be involved in transcriptional regulation and mitogenic signaling by ET-1.
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PMID:Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src. 768 50

The mechanisms by which somatostatin exerts its widespread inhibitory actions have been investigated extensively but understood only partially. Recent studies have shown that somatostatin can inhibit gene transcription directly. In view of the critical importance of early response genes in induction of gene expression, we examined whether the action of somatostatin might be mediated by inhibition of early response genes. The products of some of these genes, such as c-fos and c-jun, are known to form a heterodimeric transcription factor complex (AP-1) that binds specifically to the consensus sequence TGAC(G)TCA. Accordingly, we examined the effects of somatostatin on c-fos gene expression and on the binding of the AP-1 complex to its specific DNA element using isolated gastric parietal cells and the GH3 pituitary cell line. In both parietal and GH3 cells, c-fos-specific mRNA was increased by agents known to act via both adenosine-3',5'-cyclic monophosphate and Ca(2+)-dependent signaling mechanisms, and octreotide significantly inhibited this response. Pertussis toxin pretreatment (200 ng/ml) reversed the inhibitory effect of octreotide. AP-1 binding activity, assessed by gel shift assays using a 32P-labeled AP-1 oligonucleotide probe, was stimulated by dibutyryl adenosine 3',5'-cyclic monophosphate and serum and inhibited by octreotide treatment. Our observations support the notion that the universal inhibitory action of somatostatin may be mediated by inhibition of expression of early response genes via a pertussis toxin-sensitive inhibitory pathway. This effect appears to lead to decreased binding of regulatory nuclear proteins to their specific DNA elements resulting, presumably, in diminished gene expression.
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PMID:Molecular basis for somatostatin action: inhibition of c-fos expression and AP-1 binding. 791 96

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.
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PMID:Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2. 866 42

The pertussis toxin (PTX) insensitive heterotrimeric G protein G12 has been implicated in mitogenesis and transformation, but its direct effectors remain unknown. To define potential signaling pathways utilized by G12, we expressed an activated mutant of its alpha subunit, Galpha12(Q229L), in HEK293 cells and examined its effects on Ras and mitogen-activated protein kinases (MAPKs). Transient expression of activated Galpha12 increased the percentage of Ras in the active, GTP-bound state, stimulated c-Jun NH2-terminal kinase (JNK) activity, and enhanced the transcriptional activity of c-Jun. Dominant negative Ras (N17Ras) inhibited Galpha12-mediated JNK activation in NIH3T3 cells but failed to do so in HEK293 cells. In contrast, dominant negative Rac (N17Rac1) inhibited JNK activation by Galpha12 in HEK293 cells as well as three other cell lines. In 1321N1 cells, where thrombin stimulates G12-dependent mitogenesis, coexpression of N17Rac1 or a dominant negative mutant of MEKK1 (MEKKDelta(K432M)) inhibits c-Jun/AP-1 sensitive reporter gene expression stimulated by thrombin or Galpha12. These data demonstrate that the alpha subunit of the heterotrimeric G protein G12, like tyrosine kinase growth factor receptors, activates Ras and recruits a signal transduction pathway involving the small GTP-binding protein Rac that leads to JNK activation.
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PMID:Galpha12 stimulates c-Jun NH2-terminal kinase through the small G proteins Ras and Rac. 866 28

In 1321N1 astrocytoma cells, thrombin, but not carbachol, induces AP-1-mediated gene expression and DNA synthesis. To understand the divergent effects of these G protein-coupled receptor agonists on cellular responses, we examined Gq-dependent signaling events induced by thrombin receptor and muscarinic acetylcholine receptor stimulation. Thrombin and carbachol induce comparable changes in phosphoinositide and phosphatidylcholine hydrolysis, mobilization of intracellular Ca2+, diglyceride generation, and redistribution of protein kinase C; thus, activation of these Gq-signaling pathways appears to be insufficient for gene expression and mitogenesis. Thrombin increases Ras and mitogen-activated protein kinase activation to a greater extent than carbachol in 1321N1 cells. The effects of thrombin are not mediated through Gi, since ribosylation of Gi/Go proteins by pertussis toxin does not prevent thrombin-induced gene expression or thrombin-stimulated DNA synthesis. We recently reported that the pertussis toxin-insensitive G12 protein is required for thrombin-induced DNA synthesis. We demonstrate here, using transfection of receptors and G proteins in COS-7 cells, that G alpha 12 selectively couples the thrombin receptor to AP-1-mediated gene expression. This does not appear to result from increased mitogen-activated protein kinase activity but may reflect activation of a tyrosine kinase pathway. We suggest that preferential coupling of the thrombin receptor to G12 accounts for the selective ability of thrombin to stimulate Ras, mitogen-activated protein kinase, gene expression, and mitogenesis in 1321N1 cells.
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PMID:Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells. 893 Aug 92

In some cell systems muscarinic receptor stimulation can induce proliferation or transformation. This phenomenon is subtype-specific (only m1 and m3 receptors are effective) and cell type dependent. In 1321N1 astrocytoma cells activation of m3 receptors stimulates phospholipase C, but does not induce DNA synthesis. In contrast the thrombin receptor, which also couples to phospholipase C, is strongly mitogenic and induces AP-1-dependent gene expression. Various experimental findings indicate that this discrepancy is not due to muscarinic receptor desensitization or blockade of growth stimulatory pathways. Muscarinic receptor number may be limiting, in particular for receptor coupling to the pertussis toxin-insensitive G-protein G12. This G-protein is required for thrombin-induced mitogenesis in 1321N1 cells and may couple selectively to the thrombin versus muscarinic receptor. In cardiomyocytes hypertrophic cell growth is induced by heterologously expressed m1 or m3 receptors but not by the endogenous m2 receptors. Studies using chimeric receptors confirm that induction of hypertrophy requires signalling through phospholipase C, but indicate that additional signals are needed to induce the morphological features of this response. We suggest that small G-proteins of the Rho subfamily, in addition to G12, mediate growth responses to G-protein-coupled receptors.
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PMID:Pathways and roadblocks in muscarinic receptor-mediated growth regulation. 912 50

Assembly of terminal complement complexes (TCC) C5b-7, C5b-8, and C5b-9 on target cells during acute and chronic inflammation induces hydrolysis of plasma membrane phospholipids and heterotrimeric G protein activation. TCC also stimulate a variety of cellular activities, which include cytokine synthesis, proto-oncogene activation, and mitotic signaling. Now we report that sublytic TCC induced Ras, Raf-1, and extracellular signal-regulated kinase (ERK) 1 activation in JY25 B cell line. When cells were exposed to C5b-9, GTP-bound Ras in anti-C5b-9 immunoprecipitates was increased 3.2-fold at 2 min, while GTP-bound Ras in anti-Ras immunoprecipitates was increased 2-fold at 10 min. Both C5b-9 and C5b-7, but not C5b6, increased Raf-1 kinase activity maximum 3.3-fold at 2 min and 2.8-fold at 5 min, respectively. ERK1 activity was 2-fold increased by C5b-9 at 2 min and by C5b-7 at 10 min, over the C5b6 level. The role of mitogen-activated protein kinase (MAPK) pathway on TCC-inducible mitotic signaling was evaluated by assessing DNA synthesis and activator protein 1 (AP-1) DNA-binding activity. The MAPK/ERK-specific inhibitor PD 098,059 abolished the C5b-9-induced DNA synthesis. Involvement of G protein in the activation of MAPK pathway by TCC was indicated by inhibition of Raf-1 and ERK1 kinase activity, as well as the DNA synthesis by pretreatment of cells with pertussis toxin. Overexpression of beta-adrenergic receptor kinase 1 carboxyl-terminal peptide in JY25 cells also inhibited Raf-1 and ERK1 activity, indicating a direct involvement of G betagamma subunits in the signal transduction generated through activation of MAPK pathway by TCC assembly in the plasma membrane.
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PMID:Activation of Ras and mitogen-activated protein kinase pathway by terminal complement complexes is G protein dependent. 912 5


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