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)

Combinations of cytokines and/or phorbol ester induce expression of Type II nitric oxide synthase (NOS) mRNA in astrocyte cultures via protein kinase mediated pathways (Simmons and Murphy: GLIA 11:227, 1994; Fernstein et al.: J Neurochem 62:811, 1994). Agonists that activate receptors linked to protein kinases did not reproduce this effect of cytokines in astrocytes. On the contrary, ATP and glutamate treatment of astrocytes prior to a combination of interleukin-1 beta and interferon-gamma markedly reduced (30-50%) subsequent NOS mRNA expression. The effect was not seen if treatment coincided with or followed cytokine activation, suggesting that ATP and glutamate were not destabilizing NOS mRNA. The effects of ATP and glutamate were additive and could be mimicked by selective receptor agonists, but were insensitive to a specific inhibitor of protein kinase C. The inhibition of cytokine-induced NOS mRNA expression caused by these agents was not the result of interference with the activation/translocation of nuclear factor-Kappa Beta by interleukin-1 beta. These results suggest that exposure of astrocytes to ATP and glutamate, both of which increase markedly in a variety of neuropathologies, could modulate the subsequent responsiveness of these cells to NOS-inducing stimuli. As such, this may be an important regulatory mechanism in the expression of Type II NOS in vivo.
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PMID:Cytokine-induced expression of type II nitric oxide synthase in astrocytes is downregulated by ATP and glutamate. 884 3

The combination of lipopolysaccharide (LPS; 100 ng/ml) and interferon-gamma (IFN-gamma; 10 IU/ml) synergistically stimulated induction of nitric oxide synthase activity in J774 macrophages, measured by nitrite accumulation during an overnight incubation. Neither the phorbol ester, phorbol 12-myristate 13-acetate (PMA; 10(-9) - 3 x 10(-6) M) nor the calcium ionophore, A23187 (10(-7) - 10(-4) M), alone or in combination, stimulated accumulation of nitrite. They were also unable to substitute for IFN-gamma in priming J774 macrophages to stimulation with LPS. Phorbol 12-myristate 13-acetate (10(-9) - 3 x 10(-6) M) produced a concentration-dependent inhibition of nitrite accumulation when added prior to stimulation with LPS and IFN-gamma, but enhanced nitrite accumulation when added 12 hours following stimulation with LPS and IFN-gamma. Of the protein kinase C inhibitors tested, staurosporine (10(-9) - 3 x 10(-6) M) and Ro 31-8220 (3 x 10(-9) - 10(-5) M) produced a powerful, concentration-dependent inhibition of nitrite accumulation when added prior to stimulation with LPS and IFN-gamma, but had only slight inhibitory effects when added 12 hours after stimulation with LPS and IFN-gamma. Chelerythrine chloride ( 10(-8) - 3 x 10(-5) M) produced only a slight inhibition of nitrite accumulation when added prior to stimulation with LPS and IFN-gamma, but slightly enhanced nitrite accumulation when added 12 hours following stimulation with LPS and IFN-gamma. The tyrosine kinase inhibitors, genistein (10(-7) - 10(-4) M) and herbimycin A (5.2 x 10(-9) - 1.74 x 10(-6) M), produced a powerful concentration-dependent inhibition of nitrite accumulation when added prior to stimulation with LPS and IFN-gamma. In contrast, herbimycin A had only a slight inhibitory effect when added 12 hours following stimulation with LPS and IFN-gamma, and genistein had no effect. When used in combination prior to stimulation with LPS and IFN-gamma, herbimycin A (1.7 x 10(-7) M) and staurosporine (3 x 10(-8) M) produced additive inhibitory effects on nitrite accumulation, but herbimycin A, together with Ro 31-8220 (3 x 10(-6) M) or chelerythrine chloride (10(-5) M), produced no further effects. These results provide strong evidence for the involvement of tyrosine kinases in the induction of nitric oxide synthase by LPS and IFN-gamma in J774 macrophages. They also suggest a role for protein kinase C, but elucidation of the precise mechanisms by which this pathway interacts with tyrosine kinase to regulate the expression of nitric oxide synthase requires further investigation.
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PMID:Involvement of tyrosine kinase and protein kinase C in the induction of nitric oxide synthase by lipopolysaccharide and interferon-gamma in J774 macrophages. 886 14

Macrophage proteinases including cathepsin B (CB) are implicated in the tissue injury of inflammatory lesions. We have previously shown that interferon-gamma (IFN-gamma) increases intracellular levels of the lysosomal proteinase, CB, in THP-1 cell primed with phorbol 12-myristate 13-acetate (PMA). We have now examined the role of protein kinase C (PKC) in this effect. Following activation with PMA, the intracellular CB activity was significantly increased in the presence of 500 U/ml IFN-gamma. With the addition of protein kinase C (PKC) inhibitors bisindolylmaleimide, staurosporine, H-7, or phloretin a reversal of the effect of IFN-gamma was noted whereas the addition of the cyclic nucleotide-dependent protein kinase inhibitors HA 1004, H-8, H-89, or cAMP-Dependent Protein Kinase (PKA) Inhibitor did not block the effect. Although diacylglycerol (DAG) did not replace PMA in the study. Diacylglycerol Kinase Inhibitor induced a more pronounced augmentation and PKC depletion inhibited the effect. This suggests that a PKC-dependent pathway is involved in the response of CB in PMA primed THP-1 cells to IFN-gamma.
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PMID:Gamma interferon induced increases in intracellular cathepsin B activity in PMA primed THP-1 cells are blocked by inhibitors of protein kinase C. 887 91

Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine that is involved in the regulation of thyroid growth and differentiated functions. The cellular and molecular mechanisms involved in mediating the effects of TNF alpha on thyroid function, however, are unknown. In a number of cell types, TNF alpha receptor binding results in the activation of specific signal transduction cascades, including protein kinase C (PKC) and the hydrolysis of sphingomyelin to ceramide. In the present study, we examined the possible role of PKC and the hydrolysis of sphingomyelin to ceramide in the regulation of TSH-induced increases in 5'-deiodinase (5'D-I) activity and 5'D-I messenger RNA (mRNA) levels in FRTL-5 cells. Further, we have recently shown that TNF alpha and interferon-gamma (IFN gamma) act synergistically to block TSH-induced increases in type I 5'D-I activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Thus, we tested the hypothesis that the activation of one or both pathways is involved in synergistic effect of TNF alpha and IFN gamma on thyroid function. In TSH-stimulated FRTL-5 cells, the addition of 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of PKC, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Incubation of FRTL-5 cells with TPA and a minimal effective concentration of IFN gamma (12.5 U/ml) in combination, however, failed to result in a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Similarly, incubation of FRTL-5 cells with sphingomyelinase (SMase), which converts sphingomyelin to ceramide, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Coincubation of FRTL-5 cells with SMase and IFN gamma failed to show a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Further, incubation of FRTL-5 cells with TPA plus SMase in the presence of IFN gamma failed to result in the synergistic inhibition of TSH-induced increases in 5'D-I activity or 5'D-I mRNA levels. The effect of TPA and SMase on TSH-induced cAMP production was examined. Low concentrations of TPA, which inhibit TSH-induced 5'D-I activity, failed to inhibit TSH-induced cAMP production or the cAMP-induced increase in 5'D-I activity. In contrast, SMase inhibited TSH-induced cAMP production in a dose-dependent manner. In the presence of IFN gamma, however, activation of either or both pathways is not sufficient to result in a synergistic inhibition of 5'D-I activity or 5'D-I gene expression. Together, our results suggest that TNF alpha-induced activation of PKC and hydrolysis of sphingomyelin can inhibit thyroid cell function. The activation of additional signal transduction pathways, however, by TNF alpha is required for the synergistic inhibition of thyroid function by TNF alpha and IFN gamma.
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PMID:Effects of ceramide and protein kinase C on the regulation of type I 5'-deiodinase in FRTL-5 rat thyroid cells. 889 73

Arachidonic acid (AA) has been implicated as an important amphiphilic co-factor in the activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neutrophils and reconstituted cell-free systems. To assess the role of AA in the activation of O2- generation in monocytic cells, we studied pre-monocytic U937 cells differentiated with 1,25-(OH)2-vitamin D3 plus interferon-gamma (IFN-gamma). AA dose-dependently enhanced phorbol myristate acetate (PMA)-stimulated O2- generation, with a maximum increase of 4,5-fold, through: (1) a more than 50% reduction of the lag-phase, defined as the time between addition of PMA and detection of O2-; and (2) a more than 60% increase in the constant rate of O2- generation. Reduction of the lag phase was associated with increased protein kinase C (PKC)-independent translocation of the cytosolic subunit of NADPH oxidase p47-phox to the cell membrane, whereas increased generation of O2- correlated with enhanced activation of PKC. The data indicate that AA increases activation of NADPH oxidase by accelerating its assembly and by co-stimulating PKC in monocytic U937 cells.
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PMID:Arachidonic acid increases activation of NADPH oxidase in monocytic U937 cells by accelerated translocation of p47-phox and co-stimulation of protein kinase C. 891 91

Cytokine-stimulated expression of inducible type of nitric oxide synthase (iNOS) seems to be regulated by various signal pathways in a cell-specific manner. In this study, we examined how it was regulated in L6 rat skeletal muscle cells. In L6 cells, the combination of interleukin-1 beta and interferon-gamma induced a marked accumulation of nitrite, a stable metabolite of nitric oxide. In parallel with this reaction, iNOS mRNA expression was achieved at a maximum between 3 and 6 h, and iNOS protein was detectable at 6 h and peaked at 24 h after stimulation. Tyrosine kinase inhibitors, herbimycin A, and genistein suppressed cytokine-induced iNOS expression and nitrite production. Forskolin, an adenosine 3',5'-cyclic monophosphate-dependent protein kinase (PKA) activator, and phorbol 12-myristate 13-acetate, a protein kinase C (PKC)-activating phorbol ester, enhanced these cytokine-induced reactions. These results indicate that iNOS expression by cytokines is mediated via a protein tyrosine kinase-dependent pathway and is positively modulated by both PKA- and PKC-dependent pathways in this cell type.
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PMID:Regulation of inducible nitric oxide synthase expression in L6 rat skeletal muscle cells. 903 8

The whole-cell configuration of the patch-clamp technique was used to study the involvement of protein kinase C (PKC) in the modulation of K+ channels in cultured microglia from newborn rats. We previously showed that 24-hr treatments with interferon-gamma (IFN-gamma) induce an increase of inward-rectifying (IR) and outward-rectifying (OR) current density and that the effect on OR was shared by bacterial lipopolysaccharide (LPS) (Visentin et al.: J Neurosci Res 42:439-451, 1995). In the present study, IFN-gamma (1-500 U/ml, 24 hr) enhanced IR current density up to threefold. The IFN-gamma effect was not detectable after shorter treatments (1-5 hr) and was abrogated by a protein synthesis inhibitor. The PKC activator phorbol myristate acetate (PMA) also increased IR current density, whereas the inactive alpha-4 isoform was ineffective. When IFN-gamma and PMA were co-applied, the effect was more than additive. Among the PKC inhibitors tested, staurosporine (STA)-but not calphostin C (CALP)-abolished the effect of IFN-gamma and of PMA and antagonized only partially that of co-applied IFN-gamma and PMA. OR currents were affected by treatment (24 hr) with PKC modulating agents in an opposite fashion. PMA depressed OR currents in control and in IFN-gamma (or LPS) treated cultures, even when added after pretreatment (with LPS) that was long enough to enhance OR channel expression. Both STA and CALP enhanced OR density in resting and IFN-gamma-stimulated cells but did not counteract the depressing effect of PMA. In conclusion, our data on IR suggest a relationship between the IFN-gamma effect on current density and PKC activation. However, we cannot conclude with certainty that IFN-gamma acts through PKC activation. Our data on OR support an inverse relationship between PKC activation and OR current density. Nevertheless, the lack of effect of PKC inhibitors on PMA-induced OR depression suggests that PMA may, in this case, act on a target different from PKC.
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PMID:Protein kinase C involvement in the resting and interferon-gamma-induced K+ channel profile of microglial cells. 903 45

Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-amyloid peptide (A beta) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta (1-40) and its subfragment A beta (25-35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-alpha by interleukin-1, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta (1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-gamma. The A beta subfragment A beta (25-35) was ineffective in inducing TNF-alpha production. The cellular action of A beta (1-40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to A beta (1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alpha may help in developing new therapeutic strategies for Alzheimer's disease.
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PMID:Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. 904 34

Nitric oxide (NO) has been known to induce programmed cell death or apoptosis in murine macrophages, mouse splenocytes, and thymocytes. We demonstrate here that phorbol ester, a protein kinase C (PKC) activator, synergistically augments the antileukemic actions of the NO in HL-60 human promyelocytic leukemia cells. Exposure of cells to sodium nitro-prusside (SNP; 0.5 to 2 mM), a NO-generating agent, induced time- and concentration-related increases in morphological changes, including condensation of nuclear chromatin, nuclear fragmentation, and the apoptotic peak of propidium iodide-stained nuclei by flow cytometry. Phorbol ester alone had a small effect on inducing DNA damage, whereas SNP in combination with phorbol ester at all concentrations tested markedly increased the extent of fragmentation. Maximal potentiation of fragmentation (e.g., four- to fivefold greater than that obtained with 0.5 mM SNP alone) was observed with simultaneous treatment of phorbol ester. Similar results were obtained with another commonly used NO donor agents such as SNAP (0.5 mM) and GSNO (0.5 mM). DNA fragmentation of HL-60 cells was also augmented by 100 U/ml human recombinant interferon-gamma but not by 1.5% (v/v) DMSO or 1 microM retinoic acid. The stage-2 tumor promotor mezerein also mimicked the effect of phorbol ester to induce NO-induced apoptosis. In contrast, PKC inhibitors such as staurosporine and 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine partially blocked high concentration of SNP (2-3 mM)-induced apoptosis, suggesting that activation of PKC closely relates to the potentiation of the activity of NO on HL-60 cell apoptosis. Under the same conditions, SNP in combination with phorbol ester caused apoptosis in another transformed cell line, U-937 cells, but was ineffective at inducing apoptosis in normal peripheral blood mononuclear cells. Taken together, these findings suggest that exposure of HL-60 cells to phorbol ester renders them more susceptible to NO-induced DNA damage and that this phenomenon contributes to the cytotoxic effects of the NO-PKC combination in myeloid leukemia cells.
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PMID:Potentiation of the activity of nitric oxide by the protein kinase C activator phorbol ester in human myeloid leukemic HL-60 cells: association with enhanced fragmentation of mature genomic DNA. 907 Mar 16

Intercellular adhesion molecule-1 (ICAM-1) mediates two important functional aspects of tumor biology, namely enhancement of tumor metastasis and mediation of host defense mechanisms such as lymphocyte-mediated tumor cytotoxicity. Since ICAM-1 is expressed by most renal cell carcinomas (RCC), the regulation of ICAM-1 expression is important in understanding the biological behavior of RCC. We report an investigation on ICAM-1 expression and molecular regulation by cytokines and protein kinase C activator on RCC cell lines. Of the various cytokines, tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN gamma), and phorbol myristate acetate (PMA) strongly upregulated ICAM-1 protein expression on RCC. The kinetics of ICAM-1 message induction was studied by Northern analysis of total RNA extracted from RCC and normal kidney proximal tubular (NKPT) cells. Time course studies showed that ICAM-1 mRNA was upregulated by INF gamma, TNF alpha, and PMA, plateaued after 2 h, and remained increased for up to 24 h. Although ICAM-1 mRNA in NKPT cells was upregulated by these cytokines, their messages returned to basal levels after 24 h. ICAM-1 mRNA stability assays showed that both unstimulated and stimulated RCC cells had very stable ICAM-1 mRNA up to 24 h. In order to investigate whether increased gene transcription contributes to ICAM-1 upregulation, RCC cells were treated with TNF alpha, IFN gamma, or PMA with or without simultaneous addition of actinomycin D. ICAM-1 message induction-blocking studies suggested that primary upregulation of ICAM-1 mRNA may be caused by transcriptional upregulation. These results suggest that long-lasting ICAM-1 message upregulation in response to cytokines or PMA may be due to transcriptional upregulation in the early phase and stabilization of ICAM-1 message in the later phase (after 4 h). These observations suggest that RCC may lack the normal downregulatory mechanisms which control ICAM-1 expression and may explain the high frequency of ICAM-1 expression observed on primary human RCC.
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PMID:Molecular regulation of intercellular adhesion molecule 1 (ICAM-1) expression in renal cell carcinoma. 928 30


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