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

Six cell lines, that were cloned from murine C127 cells infected by bovine papillomavirus type 1 (BPV1), were found to differ in the degree of transformation in vitro and of tumorigenicity in vivo. In these cell lines the degree of tumorigenicity was inversely correlated with IL-6 induction by IL-1 beta. Whereas the parental C127 cell line produced 15-30 U/ml of IL-6 spontaneously, none of the transformed cell lines produced significant levels of IL-6 constitutively. On induction by human IL-1 beta the parental C127 cell line produced up to 300 U/ml of IL-6, whereas the fully transformed ID14 cell line failed to produce any. The less transformed cell lines produced lower yields of IL-1 beta-induced IL-6, dependent on their degrees of transformation and tumorigenicity. Gelatinase B (96 kDa), a matrix metalloproteinase inducible by IL-1 beta, was dose-dependently regulated in the parental C127 cell line and in the weakly transformed cell line Tlc. These data suggest that transformation processes by BPV1 generally impair IL-1-regulated gene transcription. This impairment seems not to be located at the IL-1 beta receptor level, since in all the cell lines studied the numbers and affinities of the IL-1 beta binding sites were found to be comparable. This impairment seems not to be mediated by transformation-induced inactivation of the protein kinase C pathway since phorbol 12-myristate 13-acetate (PMA) induced IL-6 production equally well in all C127 cell-derived clones. It is suggested that BPV1 transformation can change the expression of host genes that might play a functional role in tumor immune surveillance and tumorigenicity in vivo.
Lymphokine Cytokine Res 1992 Aug
PMID:The induction of IL-6 and gelatinase B by IL-1 in mouse cell lines transformed with bovine papillomavirus: decreased production in tumorigenic cells. 133 1

We found previously that bovine lymph node cells (LNC) incubated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 18 h proliferate only to a limited degree on subsequent stimulation with concanavalin A (Con A), or with the comitogenic combination of Con A plus TPA. The lack of proliferation was traced to a lack of secretion of interleukin 2 (IL-2). Lack of secretion was paralleled by a decrease in IL-2 mRNA levels. In this study we further characterized how TPA pretreatment affected IL-2 mRNA production. We found that TPA depressed IL-2 mRNA accumulation in a dose-dependent manner after at least 10 h of pretreatment. In contrast, pretreatment from 4 to 6 h augmented IL-2 mRNA accumulation. Furthermore, LNC stimulated with ionomycin plus TPA were less susceptible to inhibition by pretreatment with TPA, most likely because this mitogenic combination caused a much greater amount of IL-2 mRNA than did Con A or Con A plus TPA. Finally, a protein synthesis inhibitor, cycloheximide, partially counteracted the negative effects of TPA on IL-2 mRNA accumulation and on proliferation. These results suggest that TPA, probably acting through protein kinase C, initially augments the production of IL-2 mRNA but subsequently induces mechanisms to decrease the level of mRNA.
Lymphokine Cytokine Res 1992 Feb
PMID:Characterization of the inhibition of interleukin 2 mRNA accumulation by 12-O-tetradecanoylphorbol-13-acetate in primary lymphocytes. 157 43

We have previously demonstrated that activation of protein kinase C (PKC) by phorbol esters induces selectively IgA synthesis by mouse B cells. In this study, we investigated the effects of a number of protein kinase inhibitors on IgA secretion induced by a recombinant murine IL-5 in LPS-stimulated mouse B cells. The results show that PKC inhibitors, such as sphingosine (SPH), staurosporine (STP) and H-7, blocked IL-5-induced IgA synthesis; the protein kinase A inhibitor HA-1004 and the inhibitor of calcium/calmodulin dependent protein kinase W-7 had no effect on IgA secretion induced by IL-5. The proliferation of the IL-5 sensitive B13 cell line in response to IL-5 was also inhibited by addition of SPH or STP or H-7. The data suggest an involvement of the PKC pathway in IL-5-induced B cell differentiation into IgA secreting cells.
Eur Cytokine Netw
PMID:IL-5-induced IgA synthesis by LPS-stimulated mouse B cells is prevented by protein kinase C inhibitors. 158 1

Interleukin-8 (IL-8/NAP-1), the neutrophil-activating peptide 2 (NAP-2), and formyl-peptides (fMLP) have been described as potent stimulators for human neutrophils (PMN). We have compared the mechanism of signal transduction induced by these factors during neutrophil activation (elastase release), by using activators and inhibitors and by direct measurement of the enzymatic activity of kinases. Moreover, costimulation kinetics of the combined factors were analyzed. Our results show that each of these stimulators induces elevated levels of cAMP, indicating the activation of adenylate-cyclase. Further results obtained with the kinase inhibitor H-7 and the cAMP analogue dibutyryl-cAMP (dbcAMP) gave evidence that cAMP-dependent kinases are involved in the down-regulation of the activation process. Degranulation could not be prevented by the inhibitor W-7, nor did the treatment of cells with calcium ionophore (A23187) lead to elevation of intracellular calcium levels. Both phenomena exclude the participation of calcium calmodulin-dependent kinases. Further results obtained with the novel protein kinase C (PKC) inhibitor BM 41440 as well as by direct measurement of PKC enzyme activity demonstrated the involvement of PKC in fMLP-mediated stimulation but not with IL-8/NAP-1 or NAP-2. Analysis of costimulation experiments conducted with these three factors and TPA confirmed these results and gave evidence that fMLP activates two different signaling pathways, one of which is PKC dependent, while the other is not. Moreover, our data indicate that NAP-2, IL-8/NAP-1, and fMLP use identical PKC-independent transduction mechanisms.
Lymphokine Cytokine Res 1991 Apr
PMID:Neutrophil-activating polypeptides IL-8 and NAP-2 induce identical signal transduction pathways in the regulation of lysosomal enzyme release. 165 69

NF-kappa B is a DNA-binding regulatory factor able to control transcription of a number of genes, including human immunodeficiency virus (HIV) genes. In T cells, NF-kappa B is activated upon cellular treatment by phorbol esters and the cytokine tumor necrosis factor alpha (TNF alpha). In the present work, we investigated the molecular events leading to NF-kappa B activation by TNF alpha in a human T cell line (Jurkat) and its subclone JCT6, which presents a deficiency in the PKA transduction pathway. We found that in both cell lines, both phorbol ester and TNF alpha were able to activate NF-kappa B. Phorbol activation was positively modulated by Ca2+ influx while TNF alpha activation was not. Furthermore, while PMA activation was inhibited by the PKC inhibitor staurosporin, the TNF alpha effect was unchanged. TNF alpha did not activate cAMP production and its signal was not modulated by cAMP activators. Moreover, cAMP activators did not activate NF-kappa B in Jurkat cells. Thus, TNF alpha-induced NF-kappa B activation was found to be mediated by none of the major signal-mediating kinases such as protein kinase C (PKC), protein kinase A, or Ca(2+)-regulated kinases. Furthermore, we found that cytoplasmic acidification facilitated NF-kappa B activation by both TNF alpha and PKC, by a mechanism that increases NF-kappa B/I kappa B dissociation without affecting the NF-kappa B translocation step.
Cytokine 1991 May
PMID:NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. 165 56

Interleukin 1 or tumor necrosis factor alpha can cause a transient down-modulation of epidermal growth factor (EGF) binding to quiescent fibroblast monolayers; the effect results from a reduction in EGF receptor (EGF-R) affinity and appears to be mediated by a protein kinase C (PKC)-independent mechanism. Here we show transient increases in EGF-R serine/threonine phosphorylation which are temporally coordinated with the effects on EGF binding; we also demonstrate that the cytokine-mediated phosphorylations, unlike those caused by PKC activators, have little discernible effect upon intrinsic EGF-R-associated tyrosine kinase activity. Cytokine-mediated EGF-R phosphorylation is resistant to staurosporine, an extremely potent inhibitor of PKC. Analysis of tryptic 32P-phosphopeptides reveals that Thr654, the unique site of PKC-mediated phosphorylation, is not phosphorylated in cytokine-treated cells, but a different, relatively acidic, peptide containing phosphoserine can be detected instead.
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PMID:Down-modulation of epidermal growth factor receptor affinity in fibroblasts treated with interleukin 1 or tumor necrosis factor is associated with phosphorylation at a site other than threonine 654. 168 28

Stimulation of quiescent T lymphocytes to proliferate involves a complex series of events both between and within cells. At least 70 genes are known to be induced or activated from the time of the initial stimulation until DNA synthesis. While some of these gene products, e.g., interleukin-2 (IL-2) and IL-2 receptors, are required for proliferation, others, e.g., gamma-interferon and colony-stimulating factor, are ancillary to activated T cell function. Several biochemical signal transductions are among the early events. One of the earliest is phospholipase C-mediated hydrolysis of phosphatidylinositol leading to release of diacylglycerols and inositol phosphates, which in turn activate protein kinase C and elevate intracellular free calcium levels. The discovery that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) both enhances proliferation and activates protein kinase C strengthens the evidence for a general role of protein kinase C in proliferation. Yet, the exact consequences of stimulation of protein kinase C in regard to specific proliferation proteins is still not clear. In this study, we present evidence that protein kinase C activation is directed to production of IL-2 but not to IL-2 receptors. Under conditions of TPA treatment in which protein kinase C was chronically reduced in T lymphocytes, IL-2 production was greatly depressed as were the level of IL-2 mRNA and [3H]thymidine incorporation. In contrast, these cells still expressed high affinity IL-2 receptors and proliferated when endogenous IL-2 was added. Because neither phosphatidylinositol metabolism nor Ca2+ flux was affected, the block appeared to be mediated directly or indirectly through protein kinase C.
Lymphokine Cytokine Res 1991 Jun
PMID:Negative regulation of interleukin-2 production in primary lymphocytes by 12-O-tetradecanoylphorbol-13-acetate. 171 61

In this study we have examined the effect of agents known to perturb certain signal transduction pathways on the biological responses of target cells to stimulation with interleukin-1 (IL-1). In the murine thymoma cell line EL4, IL-1 stimulation results in the secretion of interleukin-2 (IL-2), which was subsequently measured by proliferation of an IL-2-dependent cell line. Agents that elevated intracellular cAMP blocked or partially blocked IL-1 induction of IL-2 secretion, whereas agents that activated protein kinase C (PKC) resulted in a synergistic enhancement. Both pertussis and cholera toxins also inhibited IL-1-induced IL-2 secretion, although probably by acting at different levels. IL-1 simulation of human and murine fibroblasts resulted in release of prostaglandin E2. This response was inhibitable by pertussis toxin but not by cholera toxin, whereas co-stimulation of the fibroblasts with IL-1 and phorbol ester resulted in a synergistic response. Murine fibroblasts could also be stimulated to proliferate by IL-1, and this response was also inhibitable by pertussis toxin. These findings are consistent with coupling of the IL-1 receptor to a signalling pathway via a pertussis toxin substrate.
Cytokine 1991 Jan
PMID:Modification of biological responses to interleukin-1 by agents that perturb signal transduction pathways. 171 70

The 2-5 A synthetase is a system of several isozymes, whose expression is induced by interferons (IFNs) at the transcriptional level. These enzymes mediate part of the antiviral effects of IFNs and are thought to have an important role in cell growth or differentiation. The different isozymes -100, 69, 46 and 40 kDa expressed in human cells, or the 105, 71 and 43 kDa expressed in mouse cells--are induced by IFNs with cell type specificity, and exhibit individual differences in their biochemical and enzymatic properties. Here we studied the effects of the tumor promoter phorbol ester (TPA), or the calcium ionophore A23187, on the pattern of expression of 2-5 A synthetase isoforms, and found a role of protein kinase C (PKC) in the adjustments of this pattern. We show that in HeLa cells the 100 kDa 2-5 A synthetase can be specifically induced by short term treatments with TPA, or with the calcium ionophore A23187. Induction of the 100 kDa form is mainly post-transcriptional. By contrast long term treatments by TPA resulting in the down regulation of PKC, or employing H7, a specific PKC inhibitor, reduced drastically the induction by IFNs of the 100 kDa enzyme in HeLa or fibroblast cells, without reducing the expression of the other forms. Moreover, using a mouse Swiss 3T3 cell line in which the cDNA coding for PKC-alpha was introduced, leading to its overexpression, we could show that the mouse 105 kDa synthetase was constitutively expressed. Thus, a direct correlation was found between the expression of PKC-alpha and the specific induction of the 105 kDa form. Neutralization of autocrine IFNs by antibodies reduces the expression of the 105 kDa species. However the autocrine IFN in the medium of the cells overexpressing PKC is not able to induce 2-5 A synthetase in control transfected Swiss 3T3 cells. Thus, IFN is probably essential for the expression of the 105 kDa synthetase but may be not produced in sufficient amounts to induce the 105 kDa protein.
Eur Cytokine Netw
PMID:Specific regulation of the 100 kDa 2-5 A synthetase by protein kinase C. 175 33

The expression of mRNA coding for IL-1 alpha and IL-1 beta was examined in human peripheral blood monocytes (PBM) to determine if the two genes are under the same mechanisms of transcriptional control and whether or not they can be regulated independently. In response to E. coli lipopolysaccharide (LPS), PBM express approximately 10-fold more IL-1 beta-specific mRNA than IL-1 alpha. However, treatment of these cells with phorbol myristate acetate (PMA) resulted in the expression of IL-1 beta mRNA. Likewise, treatment of PBM with phorbol dibutyrate (PdBu), phorbol diacetate (PDA), or mezerein, which, similar to PMA, were able to induce the translocation of protein kinase C (PKc) to the monocyte plasma membrane, resulted in predominantly IL-1 beta mRNA expression. The inactive tumor promoter 4 alpha-phorbol didecanoate (4 alpha-PDD) did not cause the translocation of PKc or induce the expression of either form of IL-1 mRNA. Following 18 h pretreatment with PMA to downregulate PKc activity, LPS was capable of inducing the expression of both forms of IL-1 mRNA, demonstrating that at least part of the response of PBM to LPS is PKc independent. These results suggest that the activation of PKc alone is sufficient to induce a high level expression of IL-1 beta but not IL-1 alpha mRNA. Furthermore, the possibility exists that another, as yet unknown, signal transduction mechanism is involved in inducing the expression of both IL-1 alpha and IL-1 beta mRNA in response to LPS.
Lymphokine Cytokine Res 1991 Oct
PMID:Differential regulation of interleukin-1 alpha and interleukin-1 beta mRNA expression in human monocytes: evidence for protein kinase C-dependent and -independent pathways. 176 43


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