Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
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PMID:Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. 753 79

STAT3 (signal transducer and activator of transcription 3) is a latent transcription factor that is activated by tyrosine phosphorylation (Tyr-705) in cells stimulated with cytokines or growth factors. Recent studies suggest that one or more cytoplasmic serine kinases also phosphorylate STAT3 and are necessary for maximal gene activation. Here we demonstrate, with a site-specific antibody, that STAT3 is phosphorylated on Ser-727 in human neutrophils stimulated with chemotactic factors (N-formyl-methionyl-leucyl-phenylalanine and complement C5a), cytokines [granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)], or a protein kinase C activator (PMA). (2-Amino-3'-methoxyphenyl)oxanaphthalen-4-one (PD 98059), an inhibitor of extracellular signal-regulated protein kinase (ERK) activation, blocked the serine phosphorylation of STAT3 induced by chemotactic factors or PMA. The drug was less effective on cytokines: it virtually abolished the response to GM-CSF that occurred 5 min after stimulation but only partly decreased those at 15-30 min and did not appreciably alter responses to G-CSF regardless of incubation time. 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H7), an inhibitor of a putative STAT3 serine kinase, and 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580), an inhibitor of p38 mitogen-activated protein (MAP) kinase, did not dampen any of these serine phosphorylation responses. We propose that neutrophils use both ERK-dependent and ERK-independent pathways to phosphorylate Ser-727 on STAT3. The former pathway is recruited by all ERK-activating stimuli, whereas the latter pathway uses an undefined serine kinase and is recruited selectively by cytokines.
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PMID:Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent pathways target STAT3 on serine-727 in human neutrophils stimulated by chemotactic factors and cytokines. 1041 33

To elucidate the role of endothelin in the regulation of vascular function, the cellular and subcellular mechanisms for the synthesis of endothelin and the function of endothelin-receptors have been studied extensively. In this article, recent results regarding these problems are reviewed. (1) Oxidatively modified low-density-lipoprotein (LDL) reduces nitric oxide (NO) release via inhibition of the high-affinity arginine transporter of endothelial cells. (2) Endothelin-1-induced vasoconstriction is mediated by Ca2+ influx through a non-selective cation channel sensitive to 1-[beta-[3-(4-methoxyphenyl) propoxyl]-4-methoxyphenethyl]-1H-imidazole HCl (SK & F96365). (3) A distinct domain of the endothelin-receptor is required for the coupling of different G(alpha)-proteins. (4) Endothelin ET(A) receptor-mediated mitogenic activity is mediated by two pathways, one classical protein kinase C(PKC)-dependent, and the other phosphoinositide 3-kinase dependent. Both stimulate mitogen-activated protein kinase (MAPK). Endothelin ET(B) receptor-mediated mitogenic activity is also mediated by the PKC-dependent pathway. In contrast, endothelin ET(B) receptor-mediates differentiation and apoptosis via G(alpha)i coupling.
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PMID:Subcellular mechanisms of endothelin action in vascular system. 1044 71

Epinephrine increased gene- and protein-expression of interleukin-6 (IL-6) and interleukin-11 (IL-11), which are capable of stimulating the development of osteoclasts from their hematopoietic precursors, in human osteoblast (SaM-1) and human osteosarcoma (SaOS-2, HOS, and MG-63) cell lines. An increase in IL-6 and IL-11 synthesis in response to epinephrine appeared to be a common feature in osteoblastic cells, but the magnitude of expression was different in these cell lines. In HOS cells treated with epinephrine, increases of IL-6 and IL-11 synthesis were inhibited by timolol (a beta-blocker), H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide; an inhibitor of protein kinase A (PKA)) and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; an inhibitor of p38 mitogen-activated protein kinase (MAPK)], but not by phentolamine (an alpha-blocker), calphostin C [an inhibitor of protein kinase C (PKC)], or PD98059 (2'-amino-3'-methoxyflavone; an inhibitor of classic MAPK), suggesting a common pathway mediated by beta-adrenergic receptors in the PKA and p38 systems involved in the signal transduction of IL-6 and IL-11. Furthermore, expression of both genes was inhibited by curcumin [an inhibitor of activating protein-1 (AP-1) activation], but not by pyrrolidine dithiocarbamate (PDTC) [an inhibitor of nuclear factor (NF)-kappaB]. The pharmacological study suggested that coinduction of the two genes in response to epinephrine occurred via activation of AP-1. The findings of the present study suggest that coinduction of IL-6 and IL-11 in response to epinephrine probably occurs via the PKA and p38 MAPK systems, leading to the transcriptional activation of AP-1 in human osteoblastic cells.
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PMID:Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human osteoblasts and human osteogenic sarcoma cells. 1117 36

The mitogen-activated protein kinase (MAPK) family consists of the p42/p44 MAPKs and the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38 MAPK. We have previously reported that the human adenosine A(1) receptor stimulates p42/p44 MAPK in transfected Chinese hamster ovary cells. In this study, we have investigated whether the endogenous adenosine A(1) receptor in the smooth muscle cell line, DDT(1)MF-2 activates p42/p44 MAPK, JNK and p38 MAPK. The adenosine A(1) receptor agonist N(6)-cyclopentyladenosine stimulated time and concentration-dependent increases in p42/p44 MAPK and p38 MAPK phosphorylation in DDT(1)MF-2 cells. No increases in JNK phosphorylation were observed following adenosine A(1) receptor activation. N(6)-cyclopentyladenosine-mediated increases in p42/p44 MAPK and p38 MAPK phosphorylation were blocked by the selective adenosine A(1) receptor antagonist 1,3-dipropylcyclopentylxanthine and following pretreatment of cells with pertussis toxin. Furthermore, adenosine A(1) receptor-mediated increases in p42/p44 MAPK were sensitive to the MAPK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), whereas p38 MAPK responses were blocked by the p38 MAPK inhibitor SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). The broad range protein tyrosine kinase inhibitors genistein and tyrphostin A47 (alpha-cyano-(3,4-dihydroxy)thiocinnamide) did not block adenosine A(1) receptor stimulation of p42/p44 MAPK. For comparison, insulin-mediated increases in p42/p44 MAPK were blocked by genistein and tyrphostin A47. The Src tyrosine kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the epidermal growth factor receptor tyrosine kinase inhibitor AG1478 (4-(3-chloroanilino)-6,7-dimethoxyquinazoline) also had no effect on adenosine A(1) receptor stimulation of p42/p44 MAPK. Furthermore, the protein kinase C inhibitors Ro 31-8220 (3-[1-[3-(2-isothioureido) propyl]indol-3-yl]-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dione), chelerythrine and GF 109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) were without effect on adenosine A(1) receptor-induced p42/p44 MAPK phosphorylation. In contrast, wortmannin and LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), inhibitors of phosphatidylinositol 3-kinase, attenuated adenosine A(1) receptor stimulation of p42/p44 MAPK phosphorylation. In conclusion, the adenosine A(1) receptor stimulates p42/p44 MAPK through a pathway which appears to be independent of tyrosine kinase activation but involves phosphatidylinositol 3-kinase. Finally, adenosine A(1) receptor stimulation in DDT(1)MF-2 cells also activated p38 MAPK but not JNK via a pertussis toxin-sensitive pathway.
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PMID:Regulation of p42/p44 MAPK and p38 MAPK by the adenosine A(1) receptor in DDT(1)MF-2 cells. 1122 88

Localized Ca(2+) transients resulting from inositol trisphosphate (IP(3))-dependent Ca(2+) release couple to spontaneous transient outward currents (STOCs) in murine colonic myocytes. Confocal microscopy and whole cell patch-clamp techniques were used to investigate coupling between localized Ca(2+) transients and STOCs. Colonic myocytes were loaded with fluo 3. Reduction in external Ca(2+) ([Ca(2+)](o)) reduced localized Ca(2+) transients but increased STOC amplitude and frequency. Simultaneous recordings of Ca(2+) transients and STOCs showed increased coupling strength between Ca(2+) transients and STOCs when [Ca(2+)](o) was reduced. Gd(3+) (10 microM) did not affect Ca(2+) transients but increased STOC amplitude and frequency. Similarly, an inhibitor of Ca(2+) influx, 1-2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl-1H-imidazole (SKF-96365), increased STOC amplitude and frequency. A protein kinase C (PKC) inhibitor, GF-109203X, also increased the amplitude and frequency of STOCs but had no effect on Ca(2+) transients. Phorbol 12-myristate 13-acetate (1 microM) reduced STOC amplitude and frequency but did not affect Ca(2+) transients. 4alpha-Phorbol (1 microM) had no effect on STOCs or Ca(2+) transients. Single channel studies indicated that large-conductance Ca(2+)-activated K(+) (BK) channels were inhibited by a Ca(2+)-dependent PKC. In summary 1) Ca(2+) release from IP(3) receptor-operated stores activates Ca(2+)-activated K(+) channels; 2) Ca(2+) influx through nonselective cation channels facilitates activation of PKC; and 3) PKC reduces the Ca(2+) sensitivity of BK channels, reducing the coupling strength between localized Ca(2+) transients and BK channels.
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PMID:Coupling strength between localized Ca(2+) transients and K(+) channels is regulated by protein kinase C. 1160 Apr 14

We have studied the effect of the ciguatera-related toxin maitotoxin (MTX) on the cytosolic free calcium concentration ([Ca(2+)]i) of human peripheral blood lymphocytes loaded with the fluorescent probe Fura2 and the regulation of MTX action by different drugs known to interfere in cellular Ca(2+) signalling mechanisms and by the marine phycotoxin yessotoxin (YTX). MTX produced a concentration-dependent elevation of [Ca(2+)]i in a Ca(2+)-containing medium. This effect was stimulated by pretreatment with YTX 1 microM and NiCl(2) 15 microM. The voltage-independent Ca(2+) channel antagonist 1-[beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenyl]-1H-imidazole hydrochloride (SKF96365) blocked the MTX-induced [Ca(2+)]i elevation, while the L-type channel blocker nifedipine had no effect. Pretreatment with NiCl(2) or nifedipine did not modify YTX-induced potentiation of MTX effect, and SKF96365-induced inhibition was reduced in the presence of YTX, which suggest different pathways to act on [Ca(2+)]i. Preincubation with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89) or genistein (10 microM) also had no effect on the MTX-induced [Ca(2+)]i increment. In contrast, the PKC inhibitor bisindolilmaleimide I (GF109203X 1 microM) potentiated the MTX effect, whereas phosphatidylinositol (PI) 3-kinase inhibition with wortmannin (10 nM) reduced the MTX-elicited Ca(2+) entry. In summary, MTX produced Ca(2+) influx into human lymphocytes through a SKF96365-sensitive, nifedipine-insensitive pathway. The MTX-induced [Ca(2+)]i elevation was stimulated by the marine toxin YTX through a mechanism insensitive to SKF96365, nifedipine or NiCl(2). It was also stimulated by the divalent cation Ni(2+) and PKC inhibition and was partially inhibited by PI 3-kinase inhibition.
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PMID:Maitotoxin-induced calcium entry in human lymphocytes: modulation by yessotoxin, Ca(2+) channel blockers and kinases. 1160 81

In hypertension, increased transmural pressure directly influences vascular smooth muscle cells and causes cell proliferation. However, the mechanisms of transmural pressure-induced proliferation of vascular smooth muscle cells are unknown. We investigated the role of various protein kinases in pressure-induced proliferation of vascular smooth muscle cells. Pressure was applied to quiescent rat vascular smooth muscle cells in culture by compressed helium gas in a loading apparatus. Pressure application increased [3H]thymidine incorporation in a time- and pressure-dependent manner and significantly increased the cell number. The pressor response was significantly suppressed by various protein kinase inhibitors for protein kinase C (bisindolylmaleimide I), tyrosine kinase (genistein), extracellular signal-regulated kinase kinase (PD98059; 2'-amino-3'-methoxyflavone) and p38 mitogen-activated protein kinases (MAPK) (SB203580; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). Pressure rapidly increased the phosphorylation and activity of extracellular signal-regulated kinases (ERK). Pressure also caused increment of phosphorylation level of p38 MAPK but not that of c-JUN N-terminal protein kinase (JNK). In ERK-deficient cells prepared by transfection of an antisense oligonucleotide for ERK, pressure-induced DNA synthesis was almost abolished. Our results suggest that activation of ERK is essential for pressure-induced DNA synthesis in rat vascular smooth muscle cells, in addition to activation of protein kinase C, tyrosine kinase and p38 MAPK. These processes could be involved in the pathogenesis of hypertension-related atherosclerosis.
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PMID:Activation of extracellular signal-regulated kinases is essential for pressure-induced proliferation of vascular smooth muscle cells. 1209 81

This study investigated the role of p44/42 and p38 mitogen-activated protein kinase (MAPK) in cyclooxygenase-2 expression caused by lipoteichoic acid in human pulmonary epithelial cell line (A549). Lipoteichoic acid-induced increases in cyclooxygenase activity and cyclooxygenase-2 expression were attenuated by tyrosine kinase inhibitors (genistein and tyrphostin AG126), a MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor [2'-amino-3'-methoxyflavone] (PD 98059) and a p38 MAPK inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] (SB 203580). Lipoteichoic acid-induced p44/42 MAPK activation was inhibited by protein kinase C (PKC) inhibitors [12-(2-cyanoethyl)6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] (Go 6976) and [3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide]] (Ro 31-8220), genistein and PD 98059. Lipoteichoic acid-induced increase in p38 MAPK activity was inhibited by Go 6976, Ro 31-8220, genistein and SB 203580. Lipoteichoic acid-mediated formation of nuclear factor-kappa B (NF-kappa B)-specific DNA-protein complex was inhibited by genistein, tyrphostin AG126, PD 98059 and SB 203580. These results suggest that the activations of both p44/42 and p38 MAPK by lipoteichoic acid result in stimulation of NF-kappa B-specific DNA-protein binding and subsequent cyclooxygenase-2 expression in A549 cells. Both events required activation of upstream tyrosine kinase and PKC.
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PMID:Lipoteichoic acid-induced cyclooxygenase-2 expression requires activations of p44/42 and p38 mitogen-activated protein kinase signal pathways. 1217 2

It has been known that endothelin-1 (ET-1) exerts important actions in gastrointestinal smooth muscle motility, but its precise mechanism remains unsolved. We investigated the intracellular mechanism of ET-1-induced circular smooth muscle cell contraction in cat esophagus. ET-1 produced contraction of smooth muscle cells isolated by enzymatic digestion. The contraction in response to ET-1 was concentration-dependent. Pertussis toxin (PTX) blocked contraction induced by ET-1 in intact cells. To identify the specific G protein involved in the contraction, muscle cells were permeabilized with saponin. The G(i3) or G(beta) protein antibody inhibited the contraction. Neomycin phospholipase C (PLC) inhibitor inhibited the contraction, but 7,7-dimethyleicosadienoic acid (phospholipase A(2) inhibitor) and p-chloromercuribenzoic acid (phospholipase D inhibitor) had no effects. Incubation of permeabilized cells with PLC-beta(3) isozyme antibody inhibited the contraction. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine, chelerythrine [protein kinase C (PKC) inhibitor], or genistein (protein tyrosine kinase inhibitor) inhibited the contraction, but not by diacylglycerol (DAG) kinase inhibitor, R59949. To test whether the contraction may be PKC isozyme-specific, we examined the effect of PKC isozymes antibodies on the contraction. PKC-epsilon antibody inhibited the contraction. To characterize further the specific PKC isozymes that mediate the contraction, we used, as an inhibitor, N-myristoylated peptides (myr-PKC) derived from the pseudosubstrate sequences of PKC-alphabetagamma, -alpha, -delta, or -epsilon. myr-PKC-epsilon inhibited the contraction, confirming that PKC-epsilon isozyme is involved in the contraction. To examine whether mitogen-activated protein kinases (MAPKs) mediate the contraction, specific MAPK inhibitors [MAPK kinase inhibitor, PD98059, (2'-amino-3'-methoxy-flavone), and p38 MAPK inhibitor, SB202190 (4-4-fluorophenyl) 2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole)] were used. PD98059 or SB202190 blocked the contraction. ET-1 increased the intensity of the detection bands identified by immunological methods as MAPK monoclonal p44/p42 peptides. PD98059 decreased the intensity of the detection bands compared with ET-1. In conclusion, ET-1-induced contraction in cat esophageal circular muscle cells depends on PTX-sensitive G(i3) protein and PLC-beta(3) isozyme, resulting in the activation of PKC-epsilon- or protein-tyrosine kinase-dependent pathway, subsequently mediating the activation of p44/p42 MAPK or p38 MAPK pathway.
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PMID:The signal transduction of endothelin-1-induced circular smooth muscle cell contraction in cat esophagus. 1218 48


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