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)

Northern analysis of poly(A)+ RNA extracted from J774 cells (a mouse macrophage cell line) showed that this cell line constitutively expresses mRNAs specific for protein kinase C (PKC)-beta I, -beta II, -epsilon and -zeta, but not those for PKC-alpha, -gamma or -delta. Western analysis of the total cell lysate showed that J774 cells express PKC-beta II, -epsilon and -zeta isoenzymes, but failed to show the expression of PKC-beta I. The exposure of J774 cells to > 10 nM PMA led to a loss of immunoreactive PKC-beta II in 4 h. The down-regulation of immunoreactive PKC-epsilon required more than 8 h of the exposure to > 100 nM PMA. Immunoreactive PKC-zeta was most resistant to PMA treatment and was not significantly reduced after the exposure to 300 to 600 nM PMA for 24 h. PMA-mediated, persistent down-regulation of PKC-beta II is probably a result of the inhibition of PKC-beta II biosynthesis at the posttranscriptional level, because PMA-exposed cells were found to gradually increase the expression of PKC-beta II specific mRNA. PMA-pretreated cells responded to a low dose (10 ng/ml), but not to a high dose (1 microgram/ml), of LPS by significantly lower expression of mRNA specific for the inducible nitric oxide synthase (i-NOS) gene and production of nitric oxide (NO) than the control cells did. Thus, PKC could be a part of the signal transduction apparatus involved in LPS-induced inducible nitric oxide synthase gene activation.
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PMID:Properties of protein kinase C isoforms (beta II, epsilon, and zeta) in a macrophage cell line (J774) and their roles in LPS-induced nitric oxide production. 750 30

Many membrane proteins are implicated in the control of cell function by triggering specific signaling pathways. There is a new family of membrane proteins, defined by its structural motifs, which includes several lymphoid antigens, but lacks a function. To study its biological role, we determined which signaling pathways are affected by the CD53 antigen, a prototypic member of this family, in rat macrophages. Activation of CD53 by cross-linking results in an increase in inositol phosphates and diacylglycerol and in Ca2+ mobilization, which are insensitive to pertussis or cholera toxins. There is a translocation of protein kinase C to the membrane accompanied by nitric oxide (NO) release in macrophages. This effect is the result of the expression of the inducible nitric oxide synthase (iNOS), which is dependent on protein kinase C and protein synthesis. These results have linked a new receptor with a specific pathway of NO induction and thus have opened up a novel aspect of NO regulation in cell biology.
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PMID:Induction of nitric oxide release by MRC OX-44 (anti-CD53) through a protein kinase C-dependent pathway in rat macrophages. 751 80

The murine macrophage cell line, J774, when activated with interferon-gamma (IFN-gamma), expressed high level of inducible nitric oxide synthase (iNOS) and bound significantly more [3H]-phorbol-dibutyrate (PBu2) compared to non-activated cells. The increased PBu2 binding to the particulate fraction of the cells is a measure of activation and translocation of protein kinase C (PKC). Both the expression of iNOS and the enhanced. PBU2 binding in the activated J774 cells were significantly inhibited by the pretreatment of the cells with murine recombinant interleukin-4 (IL-4). Stimulation of J774 cells by IFN-gamma and lipopolysaccharide results in the translocation predominantly of the epsilon isoform of PKC (PKC-epsilon), and this is inhibited by IL-4. The inhibition of PKC activation was also evident by measuring the PKC activity in the cytosolic-fraction of the IL-4-treated cells. Activated J774 cells pretreated with IL-4 or a PKC-specific inhibitor (RO31-8220) failed to express mRNA of iNOS analyzed by PCR. These results, therefore, suggest that the inhibition of nitric oxide synthesis in activated murine macrophages by IL-4 is at the transcriptional level and may involve the inhibition of the activation of PKC-epsilon.
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PMID:Inhibition of nitric oxide synthesis by interleukin-4 may involve inhibiting the activation of protein kinase C epsilon. 752 36

Increased blood flow and vascular permeability of early diabetes have been associated with increased nitric oxide formation in diabetic rats, but the specific nitric oxide synthase responsible is unknown. We examined the modulation of the induction and activity of the inducible NOS isoform by high glucose concentration in a murine macrophage cell line, RAW 264.7, and murine glomerular mesangial cells. Culturing both cell types in high glucose concentration led to significant increases in nitrite production and the mRNA encoding iNOS upon stimulation with LPS plus interferon-gamma, as compared with normal glucose concentration. High glucose also modestly enhanced LPS/IFN-gamma-induced stimulation of the iNOS promoter in transient transfection experiments in mesangial cells. Protein kinase C activation led to enhanced mRNA expression of iNOS, and inhibitors of protein kinase C blocked nitrite accumulation in mesangial cells. These findings suggest that high glucose in combination with stimulation by LPS plus IFN-gamma enhances iNOS expression, and protein kinase C activation may be playing a role in this enhancement.
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PMID:Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C. 753 75

The present study characterizes mechanisms involved with the induction of nitric oxide (NO) production, nitric oxide synthase (NOS) enzymatic activity and mRNA expression in human articular chondrocytes. Activation of chondrocytes with lipopolysaccharide (LPS) or IL-1 resulted in time- and dose-dependent increases in iNOS mRNA followed by increased NOS enzymatic activity and NO release. The protein tyrosine kinase (PTK) inhibitors herbimycin A or genistein reduced IL-1 or LPS-induced NO release and NOS enzymatic activity. This was associated with inhibition of iNOS mRNA expression as determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. In contrast, inhibitors of protein kinase C (PKC) or protein kinase A (PKA) did not affect these responses. These results were confirmed in experiments with second messenger agonists where neither activation of PKC, nor increases in cyclic adenosine monophosphate (cAMP) or increased intracellular calcium levels were associated with the induction of iNOS mRNA or NO release. These results suggest that PKC, PKA and calcium-dependent signals are not required or sufficient for the stimulation of NO production. However, NO production is dependent on tyrosine kinases due to their role in the expression of iNOS mRNA.
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PMID:Tyrosine kinases are involved with the expression of inducible nitric oxide synthase in human articular chondrocytes. 753 12

To elucidate whether cytokines induce nitric oxide synthase in vascular smooth muscle cells, we studied the effects of human recombinant interleukin-1 beta on the synthesis and release of nitric oxide in cultured rat vascular smooth muscle cells by measurement of NO2-/NO3- levels. Furthermore, we performed Northern blot analysis using subcloned polymerase chain reaction products as probes for constitutive and inducible nitric oxide synthase. Interleukin-1 beta dose dependently (1 to 20 ng/mL) stimulated NO2-/NO3- production as a function of time. Northern blotting demonstrated the interleukin-1 beta-induced expression of messenger RNA for an inducible but not for the constitutive nitric oxide synthase after 3 hours. NG-Monomethyl L-arginine completely blocked the interleukin-1 beta-induced NO2-/NO3- production, the effect of which was reversed by L-arginine but not by D-arginine. Dexamethasone inhibited the interleukin-1 beta-induced NO2-/NO3- production in a dose-dependent manner (10(-9) to 10(-7) M) and the interleukin-1 beta-inducible nitric oxide synthase messenger RNA levels. Neither a calmodulin inhibitor (W-7) nor a protein kinase C inhibitor (staurosporine) showed any effects on the induction of nitric oxide synthase transcripts or production of NO2-/NO3- stimulated by interleukin-1 beta, whereas cycloheximide and actinomycin D completely inhibited the basal and stimulated NO2-/NO3- production. These data demonstrate for the first time that interleukin-1 beta induces gene expression of inducible nitric oxide synthase and its de novo protein synthesis in rat vascular smooth muscle cells, thereby leading to generation of nitric oxide via Ca2+/calmodulin-independent and protein kinase C-independent mechanisms.
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PMID:Induction of nitric oxide synthase gene by interleukin in vascular smooth muscle cells. 768 32

Adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC) both express an inducible nitric oxide synthase (iNOS or NOS2) following exposure to soluble inflammatory mediators. However, NOS2 gene expression is regulated differently in response to specific cytokines in each cell type. Interleukin-1 beta (IL-1 beta) induces NOS2 in both, whereas interferon gamma (IFN gamma) induces NOS2 expression in myocytes but not in CMEC. Therefore, we examined the specific signal transduction pathways that could regulate NOS2 mRNA levels, including activation of 44- and 42-kDa mitogenactivated protein kinases (MAPKs; ERK1/ERK2) and STAT1 alpha, a transcriptional regulatory protein linked to cell membrane receptors. Although IL-1 beta treatment increased ERK1/ERK2 activities in both cell types, IFN gamma activated these MAPKs only in myocytes. STAT1 alpha phosphorylation, consistent with IFN gamma-induced signaling, was readily apparent in both cell types, and binding of activated STAT1 alpha from cytoplasmic or nuclear fractions from IFN gamma-treated adult myocytes to a sis-inducible element could be demonstrated by gel-shift assay. The farnesyl transferase inhibitor BZA-5B blocked activation of ERK1/ERK2 and induction of NOS2 by IFN gamma and IL-1 beta in myocytes. IL-1 beta and IFN gamma-induced NOS2 gene expression in myocytes was also down-regulated by both protein kinase C (PKC) desensitization and by the PKC inhibitor bisindolylmaleimide, implicating PKC-linked activation of Ras or Raf in the induction of NOS2 by IL-1 beta and IFN gamma in cardiac muscle cells. In CMEC, the MAPK kinase inhibitor PD 98059 blocked activation of ERK1/ERK2 and down-regulated IL-1 beta-mediated NOS2 induction, whereas activation of ERK2 in the absence of cytokines by okadaic acid, an inhibitor of phosphoserine protein phosphatases, also induced NOS2 mRNA. These data demonstrate that ERK1/ERK2 activation appears to be necessary for the induction of NOS2 by IL-1 beta and IFN gamma in cardiac myocytes and CMEC. In the absence of ERK1/ERK2 activation by IFN gamma in CMEC, phosphorylation of STAT1 alpha is not sufficient for NOS2 gene expression. These overlapping yet distinct cellular responses to specific cytokines may serve to target NOS2 gene expression to specific cells or regions within the heart and also provide for rapid escalation of NO production if required for host defense.
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PMID:Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. 855 38

Transcription factor NF-kappaB is essential for the induction of nitric oxide synthase (NOS) II (iNOS) by bacterial lipopolysaccharide in murine macrophages (Xie, Q. W., Kashiwabara, Y., and Nathan, C. (1994) J. Biol. Chem. 269, 4705-4708). In 3T3 fibroblasts, agents other than cytokines are efficacious inducers of NOS II expression. In addition to cytokines such as interferon-gamma or tumor necrosis factor-alpha, protein kinase C-stimulating agents such as tetradecanoylphorbol-13-acetate, or cyclic AMP-elevating agents such as forskolin and 8-bromo-cAMP markedly increased NOS II mRNA (measured by Sl nuclease and RNase protection analyses), NOS II protein (determined by Western blotting), and NOS activity (measured by chemiluminescence detection of NO2-). Transforming growth factor-beta1 (which is an inhibitor of NOS II induction in other cell types) potentiated NOS II mRNA expression produced by all inducing agents listed, whereas dexamethasone, pyrrolidine dithiocarbamate and 3,4-dichloroisocoumarin (inhibitors of NF-kappaB activation) suppressed NOS II mRNA induction in response to all stimulants. In electrophoretic mobility shift assays, nuclear protein extracts from 3T3 cells stimulated with any of the inducing agents significantly slowed the migration of an NF-kappaB-binding oligonucleotide, whereas nuclear extracts from untreated control cells did not. These experiments indicate that NF-kappaB is the key control element for the induction of NOS II in response to at least three different second messenger pathways in 3T3 cells.
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PMID:In murine 3T3 fibroblasts, different second messenger pathways resulting in the induction of NO synthase II (iNOS) converge in the activation of transcription factor NF-kappaB. 862 88

We have previously reported that interleukin-1 beta (IL-1) alone induced the transcription of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production by isolated neonatal rat cardiac myocytes (CM). The present studies were undertaken to explore the signal transduction pathways involved in IL-1-induced NO production by CM. The addition of IL-1 to CM resulted in a peak rise in both adenosine 3',5'-cyclic monophosphate (cAMP) and protein kinase A (PKA) activities by 10 min followed by rapid declines and return to basal levels within 60 min. The PKA inhibitor KT-5720 completely blocked NO-2 production by IL-1-stimulated CM (P < 0.01; n = 12). The protein kinase C (PKC) inhibitor, calphostin C, had no effect on NO2- production by IL-1 stimulated CM [P = not significant (NS); n = 12]. The addition of PKA+cAMP to cytosols derived from IL-1-treated CM did not directly enhance iNOS enzyme activity (P = NS; n = 3). CM treated with IL-1 alone stained positively for iNOS protein by immunohistochemistry. iNOS staining was absent in CM treated with IL-1+KT-5720. KT-5720 resulted in an earlier disappearance of iNOS mRNA from IL-1-treated CM, as detected by semiquantitative reverse transcriptase-polymerase chain reaction. We report for the first time that PKA (but not PKC) activation is required for IL-1-induced NO production by CM.
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PMID:Protein kinase A activation is required for IL-1-induced nitric oxide production by cardiac myocytes. 876 74

We studied the modulation of the inducible nitric oxide synthase (iNOS) in cultured rat smooth muscle cells using high concentrations of glucose. A dose-dependent decrease in the nitric oxide production induced by IL-1beta was observed when cell cultures were pretreated with high glucose. In addition, the down-regulation of nitric oxide production was also time- and dose-dependent. The decrease of nitric oxide production paralleled the decrease in the expression of iNOS. Protein kinase C inhibitor ameliorated the down-regulation of cytokine-induced nitric oxide production by high concentrations of glucose. Hyperosmolar concentrations of mannose had no effect on nitric oxide production. These findings suggest that high glucose in combination with stimulation by IL-1beta decreases iNOS expression and nitric oxide production, and protein kinase C activation may be playing a role in the inhibition of nitric oxide production by high glucose.
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PMID:Glucose-induced down-regulation of NO production and inducible NOS expression in cultured rat aortic vascular smooth muscle cells: role of protein kinase C. 895 84


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