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 expression in human fibroblasts of the beta 2-interferon (IFN-beta 2) gene, which is now recognized to be identical to the gene encoding B-cell differentiation factor BSF-2, is enhanced by several cytokines that affect cell growth (tumor necrosis factor, interleukin 1, platelet-derived growth factor, and beta 1-interferon). We have examined the possibility that IFN-beta 2 gene expression is regulated through activation, by diacylglycerol, of the protein kinase C pathway. The synthetic diacylglycerols 1,2-dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol strongly enhanced IFN-beta 2, but not IFN-beta 1, gene expression in human fibroblasts (FS-4 strain). An increase in IFN-beta 2 mRNA level was detected within 15 min after addition of diC8 (290 microM) to FS-4 cells and was maximal approximately 20 hr later. An increase in IFN-beta 2 gene transcription was detected within 5 min of addition of diC8, and the rate of transcription was near-maximal by 15-30 min. The enhancement of IFN-beta 2 gene expression by diC8, interleukin 1, or tumor necrosis factor was not prevented by H8, a preferential inhibitor of cAMP- and cGMP-dependent protein kinases, but was blocked by H7, an inhibitor of protein kinase C as well as of cyclic nucleotide-dependent protein kinases. diC8 was found to protect FS-4 cells from the cytopathic effect of vesicular stomatitis virus; this protection was blocked by polyclonal or monoclonal antibodies that neutralize IFN-beta, suggesting that the antiviral effect was due to the secretion of IFN-beta 2 by the diC8-treated fibroblasts. The calcium ionophore A23187 (1-10 microM) also elicited an increase in the level of IFN-beta 2 mRNA in FS-4 fibroblasts; appropriate combinations of A23187 and diC8 had at least an additive effect in enhancing IFN-beta 2 mRNA levels. These results show that protein kinase C-activating or [Ca2+]-elevating agents rapidly increase the expression of the IFN-beta 2 gene in human fibroblasts.
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PMID:Rapid enhancement of beta 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. 310 77

We investigated the effects of human interferon(IFN)-beta and -gamma on protein kinase C activity in human HEp-2 and KHm-14 tumor cells during IFN-induced inhibition of cell growth. Cytosolic protein kinase C activity in both cell lines was strikingly decreased following treatment with either IFN-beta or -gamma. In the particulate fraction, IFN-gamma decreased protein kinase C activity within 1 hr but it reappeared after 24 hr, whereas IFN-beta decreased the activity during the inhibition of cell growth. Furthermore, phorbol-12,13-dibutyrate(PDBu)-binding activity was altered in parallel with the changes in protein kinase C activity induced by the IFNs. In summary, we showed that IFN-beta and -gamma cause long-term modulation of protein kinase C activity in these cultured tumor cells.
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PMID:Modulation of protein kinase C activity during inhibition of tumor cell growth by IFN-beta and -gamma. 312 51

We studied the effect of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma), alone and in combination, on the expression of chemotactic peptide receptors, stimulus-induced actin polymerization, hydrogen peroxide production (H2O2), and expression of nonspecific esterase (NSE) positivity in human promyelocytic leukemic cell line HL-60. These parameters were analyzed following a five-day culture with the cytokines. Chemotactic peptide receptor expression was studied using the fluoresceinated hexapeptide, formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine and flow cytometry. Actin polymerization, an important event required for chemotaxis and phagocytosis, was studied using NBD-phallacidin labeling, following stimulation with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA). TNF increased the expression of chemotactic peptide receptors in a dose-dependent fashion, and there was good correlation between the receptor expression, stimulus-induced actin polymerization, H2O2 production, and NSE positivity. IFN-gamma was less potent in inducing all the parameters studied but exerted a positive cooperative effect when combined with TNF. IFN-gamma at high concentrations induced chemotactic peptide receptors comparable in magnitude to that seen with TNF but failed to prime these cells to undergo actin polymerization in response to FMLP or PMA. Undifferentiated HL-60 cells showed a decrease in F-actin content on stimulation with PMA. This suggests that protein kinase C might have a negative regulatory role in stimulus-induced actin polymerization. The observations reported here indicate that appropriate combinations of different inducing agents with different modes of action might be necessary to duplicate the functional abilities of mature phagocytic cells.
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PMID:Cooperative effect of tumor necrosis factor and gamma-interferon on chemotactic peptide receptor expression and stimulus-induced actin polymerization in HL-60 cells. 312 45

Biochemical events that follow the engagement of cytotoxic T lymphocytes (CTL) with an Ag-bearing target cell (TC) or triggering by the crosslinking of the Ag-receptor (TcR) by immobilized anti-TcR mAb were studied using cloned CTL and a novel CTL activation assay. The approach described here was undertaken to shed light on the molecular mechanisms of "ON", "STOP" and "OFF" signalling that allow CTL to be activated, kill TC and disengage from the target cell after delivery of the "lethal hit" and then to proceed with the destruction of the next Ag-bearing target encountered. Biochemical studies of TcR-regulated and TcR-triggered constitutive exocytosis in CTL provided a detailed description of the molecular requirements for this important phenomenon in T lymphocytes and provided an alternative CTL activation assay; this assay measures the TcR-dependent response in the absence of a TC. These studies also helped to envision CTLs screening activities as a cycle of engagements-disengagements with the TC, where every surrounding cell is treated by the CTL as a potential Ag-bearing TC. Both constitutive and regulated exocytosis in CTL are triggered through a transmembrane signalling pathway which involves protein kinase C and extracellular Ca2+ that, most likely, is translocated through Ca2+ channels. This is followed by the involvement of calmodulin (CaM)-binding proteins, e.g., calcineurin, a CaM-dependent phosphatase, which was shown to be a major CaM-binding protein in murine lymphocytes. Unexpectedly, these biochemical studies demonstrated that the granule exocytosis model of CTL-mediated cytotoxicity cannot account for the mechanism of target cell lysis by CTL, at least in in vitro conditions in the absence of extracellular Ca2+. These results indicate the existence of an extracellular Ca2+-independent, TcR-regulated CTL response and raise the possibility that second messenger(s) other than Ca2+ and/or products of phosphoinositide turnover are involved in T-cell lysis. Predominance of "non-lethal" engagements between some CTL and TC, revealed during time-lapse cinematographic studies, together with comparative studies of TcR-regulated exocytosis of granules and of constitutive exocytosis of gamma-interferon, suggested that TC destruction by CTL may not be their only or even their most important function in vivo. It is possible that CTL, triggered by Ag recognition to exocytose storage granules and to synthesize and constitutively exocytose macrophage-activating factors, in turn promote tumor destruction by macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanistic, functional and immunopharmacological implications of biochemical studies of antigen receptor-triggered cytolytic T-lymphocyte activation. 313 92

Interleukin-2 (IL-2) is a chemically defined lymphokine (LK) available as mixed human (LK) preparations, as partially purified lymphoblastoid IL-2, or as recombinant human IL-2. Each has different actions dependent on companion LKs showing synergistic interaction (e.g., IL-1 and gamma-interferon (gamma-IFN]). IL-2 acts to expand activated T cells; to activate natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytolytic T cells (CTL); to regulate T-cell ontogeny via actions on prothymocytes and immature T cells; and to induce gamma-IFN and activate tumoricidal macrophages. IL-2 acts via specific cell surface receptors on protein kinase C and cyclic GMP-related mechanisms. While stable, its in vivo half-life is short and its persistence is important for it to induce a response. Toxicities include an influenzia-like syndrome, anemia, eosinophilia, and fluid accumulation. In vivo actions include augmentation of cytotoxic responses at high doses, T-cell adjuvant actions, and T-cell restorative actions at midrange doses and at low doses with companion LKs. Antitumor responses in man and animals occur, but irregularly. They are maximized by the concomitant use of LAK cells, cytoreductive therapy, antisuppressor cell therapy, and regional or persistent administration. IL-2 offers hope for more effective therapy of cancer and a variety of immunodeficiency diseases involving IL-2 defects, including AIDS, viral infections, and autoimmune diseases.
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PMID:Recent advances in the preclinical and clinical immunopharmacology of interleukin-2: emphasis on IL-2 as an immunorestorative agent. 314 Oct 54

The role of macrophages in the regulation of inflammation and immunity is, in part, due to their secretory repertoire. Among the important mediators released by macrophages are the products of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid (20:4) metabolism. The principal focus of this paper is the mechanism by which bacterial lipopolysaccharides (LPS) regulate 20:4 metabolism in macrophages. LPS has the capacity to prime macrophages for greatly enhanced 20:4 metabolism when the cells are subsequently challenged with a spectrum of triggers. Concomitant with priming, LPS also promotes the covalent attachment of myristic acid to a set of macrophage proteins. The time and concentration dependence of LPS-induced protein myristoylation is consistent with a role for myristoylation in LPS priming of the 20:4 cascade. One of the myristoylated proteins is a 68K (K = 10(3) Mr) protein kinase C substrate which associates with membranes upon myristoylation. LPS-primed macrophages show greatly increased phosphorylation of the 68K protein when the cells are subsequently treated with protein kinase C activating phorbol esters. It is proposed that the myristoylation of the 68K protein promotes its attachment to the membrane where it is more closely associated with activated protein kinase C (PKC), an association which would ensure more efficient catalysis during the mobilization and oxygenation of 20:4. This paper also examines protein myristoylation during T-cell-mediated activation of macrophages. Immune-activated macrophages have an enhanced capacity to kill several infectious agents by oxidative mechanisms. The lymphokine gamma-interferon (IFN gamma) rapidly induces the myristoylation of a 48K protein. This 48K protein is also myristoylated in murine macrophages that have been activated in vivo by intraperitoneal injection of Corynebacterium parvum, suggesting that it may be an important intermediate in the activation of macrophages for enhanced microbicidal capacity.
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PMID:Protein myristoylation as an intermediate step during signal transduction in macrophages: its role in arachidonic acid metabolism and in responses to interferon gamma. 315 94

Interleukin-2 (IL-2) is a regulatory peptide important for the growth and differentiation of antigen-specific T lymphocytes and large granular lymphocytes. Interaction of IL-2 with its specific receptor results in the promotion of S-phase progression as well as, in certain circumstances, the production and release of gamma-interferon (IFN-gamma). Although the binding of IL-2 with high-affinity specific receptors has been well characterized, the intracellular mechanisms by which this ligand-receptor interaction promotes growth and differentiation are unknown. Here, we present evidence that IL-2/receptor interaction produces a rapid and transient redistribution of protein kinase C (PK-C) from the cytosol to the plasma membrane. Phorbol myristate acetate (PMA) also induces PK-C transposition in an analogous manner, except that PMA-induced PK-C transposition to the plasma membrane is apparently protracted. As phorbol esters have been shown to mimic IL-2 in the regulation of cellular proliferation as well as IFN-gamma production, the activation of PK-C by either phorbol esters or IL-2/receptor interaction seems to have a crucial role in signal transduction elicited by these extracellular messengers.
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PMID:Interleukin-2 stimulates association of protein kinase C with plasma membrane. 315 20

We have examined the role of protein kinase C in the anti-proliferative effects of interferon in Swiss 3T3 cells. Treatment of these cells with interferon did not stimulate the phosphorylation of an acidic Mr 80,000 cellular protein which serves as a substrate for protein kinase C. In addition, interferon did not inhibit the binding of 125I-epidermal growth factor to specific receptors or induce the expression of the proto-oncogene, c-fos in Swiss 3T3 cells. Thus, interferon does not activate protein kinase C. Moreover, interferon can still inhibit DNA synthesis in protein kinase C down-regulated 3T3 cells, indicating that the presence of this phosphotransferase is not essential for the anti-proliferative effects of interferon.
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PMID:Interferon inhibition of DNA synthesis in Swiss 3T3 cells: dissociation from protein kinase C activation. 349 78

Both leukotrienes and dibutyryl cyclic GMP can replace the interleukin 2 (IL 2) requirement for gamma-interferon (gamma-IFN) production. In this study, the Ca dependence of the IL 2 help was demonstrated by blockage of gamma-IFN production by the Ca blocker Mn, and the competitive reversal of this block by Ca. Neither leukotriene C4 nor dibutyryl cyclic GMP could reverse the Mn block, which suggests that arachidonic acid release from phospholipids is not the only Ca-dependent event in IL 2 help for gamma-IFN production. A role for calmodulin or protein kinase C in the IL 2-mediated events was suggested by the blockage of gamma-IFN production by chlorpromazine. Relatively high concentrations of Ca were able to replace the IL 2 helper effects. Consistent with this were Ca influx experiments that showed that IL 2 helper signals for gamma-IFN production involved activation of a Ca channel.
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PMID:Interleukin 2-mediated events in gamma-interferon production are calcium dependent at more than one site. 391 81

Murine macrophages activated by interferon (IFN)-gamma and bacterial lipopolysaccharide (LPS) produce large amounts of nitric oxide (NO), which is a critical mediator for a variety of biological functions. The expression of this inducible NO synthase (iNOS) involves a protein kinase C (PKC)-dependent pathway, but the mechanism for the PKC activation in this system is unclear. Through analysis of diacylglycerol (DAG) synthesis and choline metabolism in activated macrophages, direct evidence is provided that NO synthesis involves the activation of an unusual phosphatidylcholine-specific phospholipase C (PC-PLC) and not a phosphatidylinositol-specific phospholipase C (PI-PLC) or phospholipase D (PLD).
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PMID:The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN-gamma and LPS. 751 Sep 53


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