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)

This paper presents the characterization of a sugar-specific receptor on the surface of human circulating polymorphonuclear cells. With the help of fluorescent neoglycoproteins and flow cytometry, a receptor was identified as being specific for alpha-L-rhamnosyl residues. The number of receptors was 55,000/cell and their affinity reached 2 x 10(8) l mol-1. This number changed as a function of the biological state of the cells. Indeed, receptor expression was modulated by the presence of other cells. T cells and B cells increased the number of receptors on the granulocyte surface. Expression of the alpha-L-rhamnose-specific lectin was dependent on lymphocyte derived soluble factor(s), which induce(s) growth and differentiation of polymorphonuclear phagocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) specifically produced a significant increase in the number of receptors for alpha-L-rhamnose (2-10-fold/cell). This modulation was independent of protein kinase C activators such as phorbol ester, which produced no effect on alpha-L-rhamnose receptor expression. These findings demonstrate that GM-CSF may stimulate post differentiation functions and properties of mature granulocytes.
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PMID:Cell surface lectins of human granulocytes: their expression is modulated by mononuclear cells and granulocyte/macrophage colony-stimulating factor. 213 78

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) exerts stimulatory effects on hematopoietic cells through binding to specific, high-affinity receptors (Kd = 30-100 pM). By using radiolabeled GM-CSF with high specific activity, we have investigated the factors and mechanisms that regulate GM-CSF receptor expression in normal human neutrophils, monocytes, and partially purified bone marrow myeloid progenitor cells. The neutrophil GM-CSF receptor was found to rapidly internalize in the presence of ligand through a mechanism that required endocytosis. Out of a large panel of naturally occurring humoral factors tested, only GM-CSF itself, tumor necrosis factor, and formyl-Met-Leu-Phe were found to down-regulate neutrophil GM-CSF receptor expression after a 2-hr exposure at biologically active concentrations (95% +/- 1%, 34% +/- 5%, 48% +/- 8% receptor down-regulation, respectively). GM-CSF also down-regulated its own receptor on monocytes and myeloid progenitor cells. Since formyl-Met-Leu-Phe is known to stimulate neutrophil protein kinase C activity, we also tested the ability of protein kinase C agonists to modulate GM-CSF receptor expression. Phorbol 12-myristate 13-acetate, bryostatin-1, and 1,2-dioctanoylglycerol were found to induce rapid down-regulation of the GM-CSF receptor in neutrophils, monocytes, and partially purified myeloid progenitor cells, suggesting that this effect may be at least partially mediated by protein kinase C. These data suggest that certain activators of neutrophil function may negatively regulate their biological effects by inducing down-regulation of the GM-CSF receptor.
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PMID:Regulation of surface expression of the granulocyte/macrophage colony-stimulating factor receptor in normal human myeloid cells. 215 4

Colony-stimulating factor-1 (CSF-1 or M-CSF) regulates pleiotropic developmental and functional responses of macrophages and their committed bone marrow progenitors and supports the viability of cells of the mononuclear phagocyte lineage. Its actions are mediated through its binding to cell surface CSF-1 receptors (CSF-1R) that exhibit ligand-stimulated tyrosine kinase activity. CSF-1R-induced phosphorylation of intracellular protein substrates initiates a cascade of biochemical reactions that relay signals to the cell nucleus, elicit transcription of CSF-1-responsive genes and culminate in cell division. The actions of the CSF-1R kinase can be interrupted by binding of certain monoclonal antibodies to the extracellular domain of the receptor or by agents which activate protein kinase C and accelerate receptor turnover. CSF-1R is encoded by the c-fms proto-oncogene, and specific genetic alterations, which constitutively activate the receptor kinase, provide sustained signals for cell growth leading to cell transformation. Perturbations in the structure or expression of the c-fms proto-oncogene might therefore contribute to leukemia.
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PMID:Regulation of mononuclear phagocyte proliferation by colony-stimulating factor-1. 215 78

Lymphotoxin (LT) can activate human neutrophils. Using a hemolytic plaque assay to detect secretion of lactoferrin and myeloperoxidase (MPO) from single adherent neutrophils, we showed that LT induced secretion from both primary and secondary granules. Incubation of cells with cytochalasin B was required for MPO secretion, and it enhanced lactoferrin secretion. Pertussis toxin, which blocks a G-protein in the plasma membrane, inhibited LT-induced exocytosis of MPO, but not of lactoferrin. Incubation with LT did not induce any detectable changes of the cytoplasmic free [Ca2+] in neutrophils. On the other hand, secretion of granule proteins from adherent neutrophils in response to LT was blocked by loading neutrophils with quin-2 in order to increase the intracellular calcium buffering capacity. This was achieved at a concentration of quin-2, at which the secretion induced by the phorbol ester PMA and the chemotactic peptide FMLP was unaffected. Trifluoroperazine (TFP), a dual protein kinase C and calmodulin inhibitor, significantly inhibited the LT-mediated secretion of lactoferrin from adherent granulocytes. The PMA effect was unaltered by TFP under these conditions, suggesting that the inhibitory effect was on a calcium-calmodulin dependent step. The secretion induced by TNF and GM-CSF was also blocked by buffering changes in the intracellular [Ca2+] and inhibited to a similar extent by TFP. Our results suggest that calmodulin and minute changes in the cytoplasmic free [Ca2+] may be involved in a common signal transduction pathway engaged in activation of adherent neutrophils by several cytokines.
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PMID:Lymphotoxin induces secretion of granule proteins from adherent neutrophils: possible role of intracellular free calcium. 216 92

Eicosanoid release during multilineage hematopoiesis was assessed using freshly isolated mouse bone marrow cells cultured in the presence of interleukin-3 (IL-3) (10% WEHI-3 culture-conditioned medium). Cells that could release prostaglandin E2 (PGE2) when stimulated with calcium ionophore A23187, but not with phorbol ester (PMA), appeared within 4 days. The cells harvested on day 10 released 42 ng of PGE2/10(6) cells/mL after A23187 stimulation. Leukotriene B4 (LTB4) (4 ng/mL) was also detected after A23187 stimulation, but there was no detectable LTC4 (less than 0.5 ng/mL). Nonadherent bone marrow cells were isolated from 28-day cultures and cloned. All clones were strongly IL-3-dependent. Although other growth factors such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and CSF-1 failed to promote survival or support proliferation of the cells, three clones (11-1-A6, 3-2-D5, and 11-1-A1) showed significant increases in 3H-thymidine incorporation, respectively, after PMA treatment for 24 hours. Surviving cells displayed dominantly myeloid type morphology and phenotypic characteristics. The data suggest that IL-3 is important in the formation of PGE2-producing cells. In contrast to many macrophages (MO), neither the IL-3-dependent cell lines nor the IL-3-cultured bone marrow cells released significant amounts of PGE2 when stimulated with PMA or IL-3, although PMA and IL-3 both induced translocation of protein kinase C (PKC) to the membrane fraction. The lack of production of PGE2 and other eicosanoids by the PMA- and IL-3-stimulated cell lines was confirmed by measuring the release of 3H-arachidonic acid. The data suggest that in IL-3-dependent bone marrow cell lines the activation of eicosanoid metabolism requires elevated cellular Ca2+; PKC activation alone does not appear to be a sufficient stimulus.
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PMID:Calcium ionophore but not phorbol ester promotes eicosanoids release by proliferating interleukin-3-dependent bone marrow cells. 216 25

The subclone M-07e, derived from the interleukin-3 (IL-3)-responsive human myeloid cell line M-07, is strictly dependent on either IL-3 or granulocyte-macrophage-colony-stimulating factor (GM-CSF) for its growth and survival. This cell line may be regarded as a candidate model to investigate the poorly understood events triggered by growth factors binding to human hemopoietic cells. Both IL-3 and GM-CSF induce in M-07e cells an increase of ornithine decarboxylase (ODC) activity, which reaches its maximum at 24-30 h and fully depends on de novo protein synthesis. The growth factors do not elicit translocation of protein kinase C to the membrane; thus a role of the kinase in ODC induction is ruled out. An amiloride-inhibitable Na+/H+ exchanger is present in the membrane of M-07e cells; its apparent Km for extracellular Na+ is 47.77 mM; and its activity is greatly enhanced when the cytoplasm is acidified. Growth-factor-evoked ODC activation and DNA synthesis are blocked in a dose- and time-dependent manner when M-07e cells are incubated with ethylisopropylamiloride, a specific inhibitor of Na+/H+ exchanger. The exchanger does not appear to be directly activated by IL-3 or GM-CSF, but its operation is strictly required for the biological effects of these growth factors on M-07e cell line.
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PMID:Evidence for a role of the Na+/H+ exchanger in the colony-stimulating-factor-induced ornithine decarboxylase activity and proliferation of the human cell line M-07e. 217 Apr 28

Colony-stimulating factor 1 (CSF-1) is required for the survival, proliferation and differentiation of monocytes. We previously demonstrated that the CSF-1 receptor is linked to a pertussis toxin-sensitive G protein and that the induction of Na+ influx by CSF-1 is a pertussis toxin-sensitive event. The present studies have examined activation of protein kinase C as a potential intracellular signaling event induced by the activated CSF-1 receptor. The results demonstrate that CSF-1 stimulates translocation of protein kinase C activity from the cytosol to membrane fractions. This activation of protein kinase C was sensitive to pretreatment of the monocytes with pertussis toxin. Lipid distribution studies demonstrated that phosphatidylcholine (PC) is the major phospholipid in human monocytes. Moreover, the results indicate that CSF-1 stimulation is associated with decreases in PC, but not in phosphatidylinositol (PI), levels. The absence of an effect of CSF-1 on PI turnover was confirmed by the lack of changes in inositol phosphate production. In contrast, CSF-1 stimulation was associated with increased hydrolysis of PC to phosphorylcholine and diacylglycerol (DAG) in both intact monocytes and cell-free assays. Furthermore, the increase in PC turnover induced by CSF-1 was sensitive to pertussis toxin. The results also demonstrate that the induction of Na+ influx by CSF-1 is inhibited by the protein kinase C inhibitors staurosporine and the isoquinoline derivative H7, but not by HA1004.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Colony-stimulating factor 1 activates protein kinase C in human monocytes. 219 73

There has been recent interest in the synergistic interactions between the growth factors involved in the in vitro control of hematopoiesis and other cell lineages. As a convenient model system, such interactions governing the DNA synthesis in murine bone marrow-derived macrophages (BMMs) were studied. By themselves, murine colony-stimulating factor-1 (CSF-1) and recombinant murine granulocyte-macrophage CSF (GM-CSF) were stimulators of DNA synthesis in quiescent or noncycling BMMs, whereas recombinant murine interleukin-3 (IL-3) and the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), were weak mitogens. On the other hand, murine granulocyte CSF (G-CSF), concanavalin A (Con A), and lipopolysaccharide (LPS) were inactive on their own. When the quiescent BMMs were exposed to combinations of the CSFs, there were striking synergistic effects for both GM-CSF and IL-3 with suboptimal doses of CSF-1, with a smaller effect for GM-CSF with IL-3 and little or no effect for CSF-1 with G-CSF. CSF-1, GM-CSF, and IL-3 could also synergize with TPA; CSF-1 cooperated with 1-oleoyl-2-acetylglycerol (OAG), both sets of results pointing to an interaction with protein kinase C. LPS completely abolished the CSF-1-mediated stimulation of DNA synthesis. We propose that BMMs are suitable normal cells in which to examine in depth the various mechanistic possibilities for these interactions.
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PMID:Activation and proliferation signals in murine macrophages: synergistic interactions between the hematopoietic growth factors and with phorbol ester for DNA synthesis. 245 28

We have tested a panel of recombinant hematopoietic growth factors (HGF) including the interleukins (IL) 1, 2, 3, 4, and 6 and the colony stimulating factors GM-CSF, G-CSF, M-CSF for their ability to induce proliferation of precursor B acute lymphoblastic leukemia cells (ALL) from 19 patients. In Ficoll-Isopaque isolated and T cell-depleted ALL bone marrow samples, IL2 (two cases), IL3 (four cases), and GM-CSF (one case) infrequently stimulated DNA synthesis measured by 3H-thymidine (TdR) uptake, and the other recombinant growth factors completely failed to do so. In repeat experiments with ALL blasts purified by fluorescence activated cell sorting (FACS), IL2, IL3, and GM-CSF responses could not be reproduced, suggesting that nonleukemic contaminant cells, and not the ALL blasts, had been stimulated by these factors. Cocktails containing combinations of IL1-IL4 and IL6 also lacked proliferation inducing potency. Depending on the purity of the incubated ALL cell samples, an impure preparation of B cell growth factors that has been reported to contain a highly effective stimulatory activity for precursor B ALL cells induced proliferation of residual normal cells as well as the ALL cells, as was evident from combined analysis of DNA synthesis and karyotyping. Exposure of the ALL blasts to artificial activators of protein kinase C and Ca2+ mobilization resulted in significant rises in 3H-TdR uptake, suggesting that these intracellular compounds are involved in transducing signals that upregulate proliferation. Although it remains possible that some of the human recombinant growth factors promote the growth of precursor B ALL cells in combination with other stimuli, a dominant role in the regulation of proliferation of these cells cannot be attributed to any of these cytokines at the present time.
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PMID:Recombinant hematopoietic growth factors fail to induce a proliferative response in precursor B acute lymphoblastic leukemia. 249 81

Granulocyte-monocyte colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor. Mesenchymal cells produce abundant GM-CSF in response to tumor necrosis factor alpha (TNF). We wished to determine (1) what cellular pathways enhanced levels of GM-CSF mRNA, and (2) if TNF used any of these pathways. Modulation in levels of GM-CSF mRNA in human fibroblasts (WI-38) was studied by using Northern blot analysis. Markedly increased levels of GM-CSF mRNA occurred in these cells after exposure to sodium fluoride (NaF) and the effect of NaF was slightly enhanced by aluminum chloride; these results suggest that accumulation of GM-CSF mRNA can occur by activating a G-binding protein. Stimulators of protein kinase C dramatically increased levels of GM-CSF mRNA; however, blockade of protein kinase C activity did not attenuate accumulation of GM-CSF mRNA stimulated by TNF and NaF. Exposure to ouabain increased levels of GM-CSF mRNA and this effect was prominently enhanced in the presence of low concentrations of extracellular K+ and was almost abolished in high concentrations of extracellular K+. A monovalent ionophore (monensin) also increased levels of GM-CSF mRNA. Both ouabain and monensin can increase intracellular Ca++ concentration (Cai++) through Na+-Ca++ exchange. A calcium channel blocker (diltiazem) blocked the increased levels of GM-CSF mRNA mediated by ouabain, but could not block the stimulation mediated by TNF alpha. Ca++ ionophores also increased levels of GM-CSF mRNA and rapidly increased levels of Cai++. TNF did not increase Cai++ and, moreover, was able to stimulate accumulation of GM-CSF mRNA in the absence of extracellular Ca++. Taken together, we have found that several different cellular pathways can lead to prominent accumulation of GM-CSF mRNA in mesenchymal cells including (1) activation of protein kinase C, (2) increase in Cai++, and (3) stimulation of G-binding protein. Our studies show that TNF appears to increase levels of GM-CSF mRNA independent of protein kinase C activity or levels of Cai++.
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PMID:Granulocyte-macrophage colony-stimulating factor: signals for its mRNA accumulation. 250 5


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