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)

Evidence is presented that human monocytes and acute myeloblastic leukemic (AML) cells contain both high and low affinity binding sites for interleukin-4 (IL-4). On monocytes 183 +/- 132 high affinity binding sites per cell with a Kd of 60 +/- 29 pM and 1500 +/- 600 low affinity receptors with a Kd of 2.3 +/- 0.4 nM (X +/- S.D., n = 6) could be demonstrated. On AML cells (n = 11) a comparable number and binding affinity of IL-4 receptors were observed (77 +/- 36 high affinity receptors with Kd 72 +/- 31 pM and 2400 +/- 1000 low affinity receptors with Kd of 2.2 +/- 0.7 nM). In addition, no cross-competition was shown between radiolabeled IL-4 and IL-1-alpha, IL-3, IL-6, IL-7, G-CSF, and GM-CSF. Both types of receptors on monocytes as well as on leukemic blasts could be down-modulated in a similar fashion by IL-4 and activators of protein kinase C (PKC), but not by the calcium ionophore A23187. The down-modulation by PKC activators was caused by an increased internalization, degradation and release of radiolabeled IL-4 in the medium. Finally, the functionality of the IL-4 receptors were tested on AML cells with a 3H-thymidine proliferation assay. In 8/11 cases IL-4 affected AML proliferation. These data demonstrate two different binding sites for IL-4 on normal and leukemic cells, which can be modulated by external activation signals in an analogous way.
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PMID:Expression and regulation of IL-4 receptors on human monocytes and acute myeloblastic leukemic cells. 194 30

The effect of pharmacologic manipulation of protein kinase C (PK-C) activity on the response of committed human myeloid progenitor cells (CFU-GM) to recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF) was assessed. Coadministration of the PK-C activating agents, phorbol dibutyrate (PDBu) or bryostatin 1, with rGM-CSF resulted in a dose-dependent and, under some conditions, highly synergistic increase in the number of CFU-GM. With optimal combinations, colony formation far exceeded that which could be obtained with high concentrations of rGM-CSF alone. High concentrations of PDBu (e.g. greater than or equal to 50 nM), but not bryostatin 1, completely inhibited the CFU-GM response. These inhibitory effects could be reversed by bryostatin 1, but not by high concentrations of rGM-CSF. Bryostatin 1 also potentiated colony formation in response to rGM-CSF, and blocked the inhibitory effects of high concentrations of PDBu in bone marrow cells highly enriched for progenitors bearing the MY-10 antigen. The increase in CFU-GM induced by PDBu or bryostatin 1 was associated with little change in the morphologic type of colony observed. Continuous exposure of cells to the calcium ionophore, ionomycin (500 nM), reduced the number of granulocyte-macrophage colonies, but produced little change in the concentration-response of rGM-CSF and PK-C activating agents. Finally, the PK-C inhibitors H-7 and tamoxifen, when administered at concentrations exhibiting minimal inhibitory effects in the presence of rGM-CSF alone, led to no change or small increases in the numbers of colonies formed in response to rGM-CSF and bryostatin-1, and a substantial increase in the number of colonies formed in the presence of rGM-CSF and PDBu. These results suggest that PK-C activation may play a complex role in regulating the response of normal myeloid progenitors to growth factors such as rGM-CSF. They also raise the possibility that under some circumstances the phorbol ester PDBu may trigger events that inhibit the growth of myeloid progenitors, and that this process may be blocked by bryostatin 1.
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PMID:Effect of pharmacologic manipulation of protein kinase C by phorbol dibutyrate and bryostatin 1 on the clonogenic response of human granulocyte-macrophage progenitors to recombinant GM-CSF. 199 97

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

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-macrophage colony-stimulating factor, GM-CSF, potentiates superoxide generation produced by human neutrophils stimulated with fMet-Leu-Phe and platelet-activating factor, PAF, but not by phorbol 12-myristate 13-acetate (PMA) or opsonized zymosan. The potentiation is greatest in fMet-Leu-Phe-stimulated cells. This indicates that the actions of only certain receptors are potentiated by GM-CSF. Incubation of the cells with the protein kinase inhibitor H-7 or with the protein synthesis inhibitor cyclohexamide before the addition of GM-CSF does not affect the observed potentiation. The rationales behind these studies are to examine the roles of protein kinase C and protein synthesis in the action of GM-CSF. The data suggest that neither protein kinase C nor protein synthesis is necessary for GM-CSF action. On the other hand, no potentiation can be seen in the presence of cytochalasin B. Unlike intact cells, GM-CSF does not enhance superoxide production by cytoplasts stimulated with fMet-Leu-Phe. The rationale behind the use of cytoplasts is to examine the role of granules and/or nucleus in GM-CSF action, and the data indicate that one or more of these two components is necessary for the priming effect of GM-CSF. The amount of actin associated with the cytoskeleton under control of fMet-Leu-Phe-stimulated condition is the same in normal and GM-CSF-treated human neutrophils. Botulinum D toxin ADP-ribosylates a protein with a molecular weight of 22 kDa. This ribosylation is reduced in homogenates obtained from cells pretreated with botulinum D toxin or GM-CSF. Botulinum D toxin does not affect the basal or the fMet-Leu-Phe-induced rise in the intracellular concentration of free calcium in human neutrophils. GM-CSF also increases the rise in intracellular concentration of free calcium in human neutrophils stimulated with PAF or fMet-Leu-Phe. The increases are inhibited by pertussis toxin. Several important conclusion can be drawn from these data. 1) GM-CSF potentiates the rise in Ca2+i produced by PAF and fMet-Leu-Phe, and these potentiations are inhibited in pertussis-toxin-treated cells. 2) GM-CSF does not prime cytoplasts to stimulation by fMet-Leu-Phe. This suggests that the granules and/or nucleus are necessary for the priming action. 3) The priming by GM-CSF is not mediated by the H-7-sensitive protein kinase C, botulinum D-sensitive G-protein, or protein synthesis.
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PMID:Effect of granulocyte-macrophage colony-stimulating factor on superoxide production in cytoplasts and intact human neutrophils: role of protein kinase and G-proteins. 254 9

The polypeptide hormones governing the proliferation and differentiation of the mature immune system and hematopoiesis are collectively referred to as lymphokines. We have examined a number of biochemical and molecular events stimulated by several unique lymphokines which exhibit proliferative activity on lymphoid and myeloid cell lines. Interleukin-2 (IL-2) and several members of the colony-stimulating factors (IL-3, G-CSF, and GM-CSF) stimulate similar patterns of cellular phosphorylation including the prominent phosphorylation of a 68-kDa substrate present in numerous distinct lineage cell lines. The 68-kDa substrate is phosphorylated by protein kinase C on threonine residues and is primarily cytosolic. Another kinase system activated by either physiological ligand or synthetic diacylglycerol phosphorylated the 40S ribosomal protein in a dose-dependent manner. The increased phosphorylation of S6 protein was associated with enhanced chain elongation in vitro. The kinase responsible for the in situ phosphorylation, however, was not protein kinase-C (PK-C) but another physicochemically distinct Mg2+-dependent enzyme (termed S6 kinase). These studies suggested that, although PK-C was activated by diacylglycerol, another kinase, S6 kinase, was the effector enzyme involved in the phosphorylation of the 40S protein. IL-2 and all other CSFs tested stimulated the transcription of the nuclear protooncogenes c-fos, c-myc, and c-myb. In addition, ornithine decarboxylase mRNA accumulation was also stimulated. Phorbol esters also stimulated similar gene expression; however, cyclic AMP analog inhibited phorbol ester or ligand-induced c-myc expression and ODC mRNA accumulation. Cyclic AMP agonists are antiproliferative to all the growth factors tested. We have constructed complementary oligonucleotides, "antisense", against c-fos, c-myc, and other structural genes induced by the growth factors. Such antisense oligomers were capable of selectively deleting protein expression of the respective gene products and inhibited the biological action of the growth factors.
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PMID:The molecular basis of immune cytokine action. 265 49

Human neutrophils were incubated with granulocyte-macrophage (GM)-CSF and examined for changes in second messenger systems. Twofold increases in cGMP but not cAMP were measured after 5 to 20 min with 100 U/ml GM-CSF. Guanylate cyclase activities in membrane and cytosol fractions were increased to the same extent whether measured in the presence of Mg2+ or Mn2+, or in the cytosol with Mg2+ + N-methyl-N'-nitro-N-nitroso-guanidine. Kinetic studies of the cytosol enzyme showed no changes in the Km values for Mg2+ and Mn2+dependent guanylate cyclase activities (0.91 and 0.022 mM, respectively), whereas Vm values were increased after treating intact cells with GM-CSF. Two peaks of guanylate cyclase activity were observed, one at 10 and another at 60 min after adding 100 U/ml GM-CSF, whereas only one peak at 5 min occurred with 1 U/ml. Adenylate cyclase activity was reduced by nearly 50% after adding 100 U/ml GM-CSF for 10 to 30 min. These effects were also seen in the presence of several hormonal and nonhormonal adenylate cyclase stimulators. In contrast, small increases in adenylate cyclase activity occurred after adding 1 U/ml GM-CSF. In experiments to examine the pathway of guanylate cyclase activation by GM-CSF, we observed no changes in inositol phosphates, intracellular calcium ion, or cytosolic protein kinase C. The augmentation of chemotactic peptide-induced superoxide production by GM-CSF concentrations, may be related to the effects of the higher levels of GM-CSF to stimulate late increases in guanylate cyclase or decreases in adenylate cyclase.
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PMID:Stimulation of guanylate cyclase activity and reduction of adenylate cyclase activity by granulocyte-macrophage colony-stimulating factor in human blood neutrophils. 289 92

The polypeptide hormones that govern the proliferation and differentiation of the mature immune system and hematopoiesis are collectively referred to as lymphokines. We have examined a number of biochemical and molecular events stimulated by several unique lymphokines that exhibit proliferative activity on lymphoid and myeloid cell lines. IL-2 and several members of the colony-stimulating factors (multi-CSF, G-CSF, and GM-CSF) stimulate a similar pattern of cellular phosphorylation, including the prominent phosphorylation of a 68-kD substrate present in numerous distinct lineage cell lines. The 68-kD substrate is phosphorylated by protein kinase C on threonine residues and is primarily cytosolic. Another kinase system activated by either physiological ligand or synthetic diacylglycerol phosphorylated the 40S ribosomal S6 protein in a dose-dependent manner. The increased phosphorylation of S6 protein was associated with enhanced chain elongation in vitro. The kinase responsible for the in situ phosphorylation, however, was not protein kinase C but another physicochemically distinct Mg++-dependent enzyme (termed S6 kinase). These studies suggested that although protein kinase C was activated by diacylglycerol, another kinase, S6 kinase, was the effector enzyme involved in the phosphorylation of the 40S protein. IL-2 and all other lymphokines tested stimulated the transcription of the nuclear protooncogenes c-fos, c-myc, and c-myb, as well as a member of the heat shock family of proteins, HSP 70. Phorbol esters also stimulated similar gene expression; however, cAMP analogue inhibited phorbol ester- or ligand-induced c-myc expression. cAMP agonists are antiproliferative to all the growth factors tested.
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PMID:Biochemical and molecular events controlled by lymphokine growth factors. 307 55

Tumor necrosis factor (TNF) is a major regulator of AML growth in vitro and markedly enhances AML growth induced by GM-CSF/IL-3. TNF, on the other hand, suppresses the G-CSF stimulated AML cell proliferation and serves as a modulator of growth factor receptors on AML cells. It upregulates GM-CSF and IL-3 receptors by a mechanism which depends on new protein synthesis and downregulates G-CSF receptors by activation of protein kinase C (PCK). The leukemic cells from patients with acute or chronic leukemias have similar TNF receptor structures (MW 76 kD). Serum TNF levels increase in patients with both acute and chronic leukemias especially in those with advanced disease. The clinical application of TNF in association with GM-CSF or IL-3 may be of value for patients with AML.
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PMID:Tumor necrosis factor and human acute leukemia. 751 20

Stimulation of mast cells, either via the IgE receptor or with calcium ionophore triggers the production of several cytokines, such as interleukins-3, -4, -5, and -6, and GM-CSF. In PB-3c mastocytes, ionophore-induced IL-3 and GM-CSF expression is primarily the result of mRNA stabilization, and is enhanced by oncogenic ras. Apart from mobilizing calcium, the IgE receptor activation leads to production of DAG and elevation of cAMP levels, thereby activating protein kinases C and A, respectively. The influence of these two secondary messengers on cytokine production was examined using the cAMP elevating agent IBMX, the phorbol ester PMA, and the staurosporine derivative CGP 41251, which preferentially inactivates PKC. IBMX was determined to be a potent coinducer of IL-3 expression, whereas elevation of IL-6 and GM-CSF was more pronounced in PMA-treated cells. Both PMA and IBMX were shown to act posttranscriptionally on IL-3, by extending the half-life of the mRNA. Ionophore-induced cytokine expression appears to require serine/threonine kinase activity, as it could be abolished by treatment with the drug CGP 41251. Our results therefore suggest that the factors regulating cytokine expression and mRNA stability are subject to regulation by serine/threonine phosphorylation.
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PMID:Modulation of cytokine expression in PB-3c mastocytes by IBMX and PMA. 752 62


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