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)

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

The turnover of the colony-stimulating factor 1 receptor (CSF-1R), the c-fms proto-oncogene product, is accelerated by ligand binding or by activators of protein kinase C (PKC), such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The mechanisms of ligand- and TPA-induced downmodulation were shown to differ by the following criteria. First, in cells in which PKC was downmodulated, CSF-1R reexpressed at the cell surface remained sensitive to ligand but was refractory to TPA-induced degradation. Second, a kinase-defective receptor containing a methionine-for-lysine substitution at amino acid 616 at its ATP-binding site failed to undergo ligand-induced downmodulation but remained responsive to TPA. Following CSF-1 stimulation, no intermediates of receptor degradation could be immunoprecipitated with polyvalent antisera to CSF-1R. In contrast, TPA induced specific proteolytic cleavage of the receptor near its transmembrane segment, resulting in the release of the extracellular ligand-binding domain from the cell and the generation of an intracellular fragment containing the kinase domain. Two-dimensional phosphopeptide mapping demonstrated no new sites of phosphorylation in response to TPA in either the residual intact receptor or the intracellular proteolytic fragment. Therefore, PKC appears not to trigger downmodulation by directly phosphorylating the receptor but, rather, activates a protease which recognizes CSF-1R as a substrate.
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PMID:Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms. 252 80

We have prepared a population of bone marrow cells that is highly enriched in neutrophil/macrophage progenitor cells (GM-CFC). Four distinct haemopoietic growth factors can stimulate the formation of mature cells from this population, although the proportions of neutrophils and/or macrophages produced varied depending on the growth factor employed: interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) stimulated the formation of colonies containing both neutrophils and macrophages; macrophage colony-stimulating factor (M-CSF) produced predominantly macrophage colonies; and granulocyte colony-stimulating factor (G-CSF) promoted neutrophil colony formation. Combinations of these four growth factors did not lead to any additive or synergistic effect on the number of colonies produced in clonal soft agar assays, indicating the presence of a common set of cells responsive to all four haemopoietic growth factors. These enriched progenitor cells therefore represent an ideal population to study myeloid growth-factor-stimulated survival, proliferation and development. Using this population we have examined the molecular signalling mechanisms associated with progenitor cell proliferation. We have shown that modulation of cyclic AMP levels has no apparent role in GM-CFC proliferation, whereas phorbol esters and/or Ca2+ ionophore can stimulate DNA synthesis, indicating a possible role for protein kinase C activation and increased cytosolic Ca2+ levels in the proliferation of these cells. The lack of ability of all four myeloid growth factors to mobilize intracellular Ca2+ infers that these effects are not achieved via inositol lipid hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a common signal associated with cellular proliferation stimulated by four haemopoietic growth factors in a highly enriched population of granulocyte/macrophage colony-forming cells. 255 52

The phosphorylation of the lipocortin-related protein, p68, found in Ca2+-dependent association with the submembranous cytoskeleton has been studied using isolated human placental syncytiotrophoblast plasma membrane vesicles. p68 undergoes rapid, cation-independent phosphorylation in unstimulated membrane vesicles which was inhibited, in a dose-dependent manner, by insulin, platelet-derived growth factor, macrophage colony stimulating factor, protein kinase C-activating phorbol esters and phosphatidylinositol-specific phospholipase C. Epidermal growth factor had no effect on overall p68 phosphorylation. Transferrin induced an increase in p68 phosphorylation. However, phosphotyrosine was detected in p68 after treatment with epidermal growth factor, macrophage colony stimulating factor or transferrin, whereas a reduction in p68 phosphorylation appeared to be restricted to serine. cAMP and both cholera and pertussis toxins inhibited p68 phosphorylation. Both toxins were synergistic with the effects of insulin and platelet-derived growth factor whilst being antagonistic to the effect of transferrin. Epidermal growth factor and both human and equine immunoglobulin G, all of which alone did not affect overall p68 phosphorylation, reduced cholera or pertussis toxin-induced inhibition of p68 phosphorylation. Several phosphatase inhibitors failed to prevent macrophage colony stimulating factor-induced reduction of p68 phosphorylation. These results indicate that (i) p68 is a potential substrate of receptor tyrosyl kinases, (ii) p68 is not phosphorylated by protein kinase C or cAMP-dependent kinase and (iii) p68 phosphorylation is inhibited by activation of multiple pathways including those employing diacylglycerol or cAMP as second messengers.
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PMID:The phosphorylation of p68, a calcium-binding protein associated with the human syncytiotrophoblast submembranous cytoskeleton, is modulated by growth factors, activators of protein kinase C and cyclic AMP. 255 24

This paper has reviewed, in a broad sense, the potential involvement of the oncogenes and their progenitors, the protooncogenes, in signal transduction pathways. The membrane-associated oncogene products appear to be connected with the generation and/or regulation of secondary messengers, particularly those associated with Ca2+/phospholipid-dependent activation of the serine/threonine kinase protein kinase C. Activation of transmembrane receptors, either through binding their native ligand or through point mutations that lead to constitutive expression, results in the expression of their intrinsic tyrosine-specific protein kinases. In PDGF-stimulated cells, this results in the increased turnover of phosphatidylinositols and the subsequent release of IP3 (Habenicht et al., 1981; Berridge et al., 1984). This coincides with activation of a PI kinase activity (Kaplan et al., 1987). Likewise, the fms product, which is the receptor for CSF-1, induces a guanine nucleotide-dependent activation of phospholipase C (Jackowski et al., 1986). Receptor functions are potentially regulated through differential binding of ligands (as proposed with PDGF), through interactions with other receptors, and through the "feedback" regulation mediated by protein kinase C. PDGF stimulation leads to modulation of the EGF receptor through protein kinase C (Bowen-Pope et al., 1983; Collins et al., 1983; Davis and Czech, 1985). Similarly, the neu product becomes phosphorylated on tyrosine residues following treatment of cells with EGF, although the neu protein does not bind EGF itself (King et al., 1988; Stern and Kamps, 1988). The tyrosine kinases of the src family are not receptors themselves, although they may mediate specific receptor-generated signals. The clck product is physically and functionally associated with the T-cell receptors CD4 and CD8, and becomes active upon specific stimulation of cells expressing those markers (Veillette et al., 1988a,b). The precise physiological role of the src family products has not been established, but their kinase activity is intrinsic to that function. The v- and c-src products are hyperphosphorylated during mitosis (Chackalaparampil and Shalloway, 1988), which correlates with periods of reduced cell-to-cell adhesion and communication (Warren and Nelson, 1987; Azarnia et al., 1988). Furthermore, pp60c-src is associated with a PI kinase activity when complexed with MTAg of polyoma virus, suggesting a function in stimulating increased turnover of the phosphatidylinositols (Heber and Courtneidge, 1987; Kaplan et al., 1987).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oncogenes, protooncogenes, and signal transduction: toward a unified theory? 269 May 95

The c-fos proto-oncogene is rapidly and transiently induced by PDGF in fibroblast and by CSF-1 in macrophages. In both cells, the breakdown of phospholipids with the ensuing activation of protein kinase C (PKC) and intracellular release of Ca2+ seems to play a role in the induction of c-fos. The transient induction of c-fos mRNA and protein by PDGF is both increased and prolonged by inhibitors of calmodulin, apparently by inhibiting the degradation of c-fos mRNA. While no response to cyclic nucleotides is observed in fibroblasts, cAMP is a strong inducer of c-fos in macrophages. In contrast to the transient induction by PKC/Ca2+, cAMP induces stable transcription of the c-fos gene for many hours, suggesting the existence of different mechanisms regulating c-fos transcription in the same cell.
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PMID:Involvement of common and cell type-specific pathways in c-fos gene control: stable induction of cAMP in macrophages. 302 38

We have investigated the effect of 8-Br-cyclic adenosine 3':5' monophosphate (cAMP), a pharmacological activator of cAMP-dependent protein kinase, on the proliferation and the nuclear proto-oncogene induction in a murine granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent myeloid cell line. Cells were growth arrested by granulocyte macrophage colony-stimulating factor and serum deprivation and were allowed to proceed in the cell cycle by addition of the lymphokine in the presence or absence of 8-Br-cAMP. 3H-thymidine incorporation assays showed that addition of 8-Br-cAMP inhibited the entry of cells into S phase and the subsequent proliferation. Northern analysis showed that 8-Br-cAMP had opposite effects on c-fos and c-myc mRNA induction. 8-Br-cAMP induced c-fos in the absence of any GM-CSF. In the presence of GM-CSF, c-fos mRNA was superinduced (30-fold induction compared to four- to fivefold by each signal alone). On the contrary, 8-Br-cAMP was not able to induce c-myc in the absence of growth factor and hardly interfered with the induction of c-myc by GM-CSF. Phorbol myristate acetate (PMA), a pharmacological activator of the lipid and CA++-dependent protein kinase C, was shown to induce nuclear proto-oncogene mRNA in the GM-CSF-dependent cell line. We investigated the effect of 8-Br-cAMP on PMA-induced c-fos and c-myc mRNA levels. When both cAMP dependent and lipid-dependent kinase systems were co-stimulated in the absence of GM-CSF, c-fos message was again superinduced (60-fold induction). On the contrary, c-myc message induction by PMA was inhibited by 80% by coactivation of cAMP-dependent protein kinase with 8-Br-cAMP. Our data indicate that an antiproliferative signal induces or even superinduces c-fos message and hardly interferes with c-myc induction, suggesting that the intracellular pathways resulting in c-fos and c-myc induction may be distinct and that two different pathways can lead to c-fos induction, with synergistic effects when both are activated.
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PMID:Regulation of proliferation in a murine colony-stimulating factor-dependent myeloid cell line: superinduction of c-fos by the growth inhibitor 8-Br-cyclic adenosine 3':5' monophosphate. 306 31

The haematopoietic growth factors multi-colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2 specifically control the production and proliferation of distinct leucocyte series. Each growth factor acts on a unique surface receptor associated with an appropriate signal-transduction apparatus. In this report we identify a 68 kDa substrate which is phosphorylated after stimulation of different cell types with multi-colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2. The 68 kDa substrate is also phosphorylated in each cell line stimulated with synthetic diacylglycerol, a direct activator of protein kinase C. Interestingly, granulocyte/macrophage colony-stimulating factor does not induce phosphorylation of the 68 kDa molecule. The 68 kDa molecule that is phosphorylated after stimulation with each ligand yielded similar peptide maps after chymotryptic digestion; furthermore, the substrate was always phosphorylated on threonine residues. Phosphorylation of the same residues in the 68 kDa substrate suggests that activation of protein kinase C is one common signal-transduction event associated with the action of multi-colony-stimulating factor, granulocyte colony-stimulating factor and interleukin 2.
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PMID:Identification of a signal-transduction pathway shared by haematopoietic growth factors with diverse biological specificity. 350 46

Granulocyte macrophage colony-forming cells (GM-CFC) have the potential to develop into either macrophages and/or neutrophils. With a highly enriched population of these cells we have found that although GM-CFC are equally responsive to macrophage colony stimulating factor (M-CSF) and stem cell factor (SCF) in terms of DNA synthesis, M-CSF stimulated the development of colonies containing macrophages in soft gel assays, while SCF promoted neutrophilic colony formation. When SCF and M-CSF were combined, mainly macrophage development was stimulated both in soft agar colony-forming assays and liquid cultures. An analysis of some potential signaling mechanisms associated with cytokine-mediated developmental decisions in GM-CFC revealed that M-CSF, but not SCF, was able to chronically stimulate phosphatidylcholine breakdown and diacylglycerol production, indicating that protein kinase C (PKC) may be involved in the action of M-CSF. Furthermore, M-CSF, but not SCF, can increase the levels of PKC alpha (PKC alpha) expression and stimulate the translocation of PKC alpha to the nucleus. When the PKC inhibitor, calphostin C, was added to GM-CFC cultured in M-CSF then predominantly neutrophils were produced, conversely PKC activators added with SCF stimulated macrophage development. The data indicate a role for PKC in M-CSF-stimulated macrophage development from GM-CFC.
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PMID:Cytokine-mediated protein kinase C activation is a signal for lineage determination in bipotential granulocyte macrophage colony-forming cells. 751 7

In the present study, we have used a human erythroleukemia cell line, TF-1, that proliferates in response to granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) to investigate the role of receptors for these cytokines in signal transduction mechanisms involved in proliferative responses. The receptors for GM-CSF, IL-3, and IL-5 each possess a cytokine specific alpha subunit, but all three share a common beta chain. Using an immunoblotting system designed to detect phosphotyrosine containing proteins and a permeabilized cell system to detect rapid changes in phosphate turnover on proteins, we show that while GM-CSF and IL-3 use tyrosine phosphorylation to mediate mitogenic signal transduction, IL-5 uses tyrosine dephosphorylation in its signaling pathway. The use of different signaling pathways by these cytokines can be confirmed in a biologic system whereby the proliferation induced in culture by GM-CSF and IL-3 is inhibited by tyrosine kinase inhibitors, but that induced by IL-5 is enhanced. Conversely, GM-CSF- and IL-3-induced proliferation is stimulated by a tyrosine phosphatase inhibitor, yet IL-5-induced proliferation is inhibited. Inhibitors of protein kinase C inhibit IL-3- and GM-CSF-, but not IL-5-induced proliferation. We suggest that, because all these cytokines share the identical beta chain of their receptors, the cytokine specific alpha chain mediates the linkage of each receptor to the individual biochemical signal transduction pathways responsible for the different biologic activities of these cytokines.
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PMID:Evidence for a signaling role for the alpha chains of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors: divergent signaling pathways between GM-CSF/IL-3 and IL-5. 754 66


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