EC:2.7.11.13 - FACTA Search

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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)

Human peripheral blood polymorphonuclear leukocytes (HPPMN) from healthy individuals are not primed and, hence, weak stimulation-dependent responses are induced by certain stimuli which bind to membrane receptors. When HPPMN were exposed to recombinant human tumor necrosis factor alpha (rHuTNF-alpha) or recombinant human granulocyte colony stimulating factor (rG-CSF), they underwent priming and the rate of superoxide anion (O.-2) generation was increased by subsequent exposure to formyl-methionyl-leucyl-phenylalanine (FMLP) or opsonized zymosan (OZ). However, the degree of enhancement was very small upon exposure to phorbol myristate acetate (PMA) or dioctanoyl glycerol (DOG). The oxygen burst induced by FMLP or OZ was inhibited by genistein and alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamid (ST638), which are inhibitors of tyrosine kinase (TK), and was enhanced by 1-(5-isoquinoline-sulfonyl)-3-methyl-piperazine (H-7) and staurosporine, which are inhibitors of protein kinase C (PKC). Without priming, however, O.-2 generation from HPPMN by high concentrations of FMLP was not inhibited strongly by genistein or ST638. On the contrary, the oxygen burst induced by PMA or DOG was stimulated by genistein or ST638 and was inhibited by H-7 or staurosporine. Furthermore, O.-2 generation by guinea pig peritoneal neutrophils, which are already primed in vivo, was induced markedly by FMLP by a mechanism which was stimulated by a low concentration of genistein or ST638. Thus, FMLP-mediated O.-2-generation of HPPMN is coupled with rHuTNF-alpha- or rG-CSF-priming and is inhibited by TK inhibitors, whereas PMA- or DOG-induced O.-2 generation is not coupled with TNF-alpha or G-CSF-priming and is inhibited by PKC inhibitors. These results suggest that both PKC and TK play critical roles in the regulatory mechanism of priming and NADPH-oxidase activation in neutrophils.
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PMID:Modulation of TNF-alpha-priming and stimulation-dependent superoxide generation in human neutrophils by protein kinase inhibitors. 131 9

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

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 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

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

We examined the effect of dibutyryl cAMP (dbcAMP) on the expression of LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and VLA-4 (CD49/CD29) and on eosinophilic differentiation of a human leukemia cell line, EoL-1. Dibutyryl cAMP induced eosinophilic differentiation of EoL-1 cells from 6-9 days after the start of culture with down-regulation of CD11a, CD18, and CD49 expression and up-regulation of CD11b expression. Changes in integrin expression, except for CD18, were seen predominantly in the fraction containing eosinophilic granule-positive cells, suggesting that the changes were dependent on eosinophilic differentiation. On the other hand, dbcAMP-induced changes of integrin expression were reversible and were not seen on day 9 when dbcAMP was removed on day 3, whereas eosinophilic differentiation was still present. A combination of G-CSF and TNF-alpha, which also induced eosinophilic differentiation of EoL-1 cells, increased CD11b expression slightly but had no significant effect on the expression of the other integrins. Butyrate and PMA up-regulated CD11b expression without eosinophilic differentiation. The results collectively suggest that the regulation of integrin expression on EoL-1 cells is partly dependent and partly not dependent on eosinophilic differentiation. The possible involvement of protein kinase A and protein kinase C in these changes is suggested.
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PMID:Effects of cyclic AMP on expression of LFA-1, Mac-1, and VLA-4 and eosinophilic differentiation of a human leukemia cell line, EoL-1. 752 82

We examined the expression of eosinophilic granules, esterase activity and CD14 in a human eosinophilic cell line, EoL-1. Unstimulated EoL-1 cells were weakly positive for nonspecific esterase, but negative for surface CD14, and contained a few eosinophilic granule-positive cells. A combination of G-CSF and TNF-alpha increased the eosinophilic granule-containing cells, but failed to increase esterase activity or CD14 expression. IFN-gamma alone or in combination with TNF-alpha enhanced nonspecific esterase activity but failed to induce CD14 expression or increase eosinophilic granule-containing cells. dbcAMP increased eosinophilic granule-containing cells, nonspecific esterase activity and CD14 expression. Specific esterase activity was not detected in any circumstances. EoL-1 cells fractionated by density gradients or CD14 expression showed nonspecific esterase activity and CD14 expression in both the eosinophilic granule-positive and negative cell populations. Forskolin and butyrate had a synergistic effect on CD14 induction and protein kinase A was suggested to play a role in dbcAMP-induced CD14 expression. A protein kinase C activator, phorbol 12-myristate 13-acetate, did not increase eosinophilic granules, nonspecific esterase activity or CD14 expression in EoL-1 cells. The results show that EoL-1 cells can express nonspecific esterase and CD14, but the expression is not necessarily restricted to cells which have differentiated into the monocyte/macrophage lineage.
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PMID:Induction of eosinophilic granules, nonspecific esterase activity and CD14 expression in the human eosinophilic leukemia cell line, EOL-1. 752 48

Severe congenital neutropenia (SCN) can be corrected in vivo by treatment with pharmacological dosages of recombinant human granulocyte colony-stimulating factor (rhG-CSF). In order to analyze the decreased chemotaxis of neutrophils from SCN patients receiving rhG-CSF, neutrophil functions essential for chemotaxis were investigated. The mobilization of cytosolic calcium ([Ca2+]i) and the functional state of cytoskeletal proteins in neutrophils from SCN patients were compared with either neutrophils from healthy donors (or, in selected experiments, from patients with cyclic neutropenia) and neutrophils from patients with chemotherapy-induced neutropenia also receiving rhG-CSF. Using flow cytometric analysis, two neutrophil subpopulations were detected in SCN patients in response to N-formylmethionine leucyl-phenylalanine (FMLP) (10(-9) M to 10(-7) M), one of which was unable to respond to this stimulus with an increase in [Ca2+]i. Whereas a homogeneous increase in [Ca2+]i in normal neutrophils occurred at 10(-9) M FMLP, neutrophils from SCN patients required 10(-6) M FMLP to respond homogeneously with an increase in [Ca2+]i. In contrast, G-CSF induced neutrophils from patients with cyclic neutropenia and from patients with chemotherapy-induced neutropenia showed a normal increase in [Ca2+]i after stimulation. The [Ca2+]i-dependent superoxide anion (O2-) generation in response to FMLP was also significantly diminished in neutrophils from SCN patients compared to normal neutrophils. However, O2- generation elicited by phorbolester (PMA), which directly activates protein kinase C (PKC), was not affected in SCN neutrophils. The total immunoreactive actin content and basal F-actin content in neutrophils from SCN patients were elevated as compared to normal neutrophils and neutrophils from patients with chemotherapy-induced neutropenia. The increase in F-actin content following FMLP activation was much lower in neutrophils from SCN patients as compared with normal neutrophils. These data suggest a defect in the signal transduction pathway in neutrophils from SCN patients between FMLP ligand-receptor interaction and Ca2+ mobilization, whereas upstream of PKC, triggered events seem to be unaffected. Therefore, [Ca2+]i-dependent neutrophil function in response to FMLP, such as actin disassembly, chemotaxis and O2- generation are diminished in SCN neutrophils. The pathomechanism responsible for the defective [Ca2+]i increase might be an initial step in understanding the underlying pathophysiology of SCN.
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PMID:Abnormal regulation in the signal transduction in neutrophils from patients with severe congenital neutropenia: relation of impaired mobilization of cytosolic free calcium to altered chemotaxis, superoxide anion generation and F-actin content. 767 87

We have examined the effect of the macrocyclic lactone protein kinase C (PK-C) activator bryostatin 1 on the proliferative capacity and lineage commitment of CD34+ human bone marrow cells exposed to the granulocyte-macrophage colony-stimulating factor/interleukin-3 (GM-CSF/IL-3) fusion protein pIXY 321. pIXY 321 administered at a dose of 10 ng/mL was as effective as the combination of plateau concentrations of recombinant (r) IL-3 and rGM-CSF (e.g., 50 ng/mL) in stimulating the growth of day-14 committed myeloid progenitors (colony-forming units granulocyte/macrophage [CFU-GM]). In the large majority of samples tested, coadministration of 0.5 to 100 nM bryostatin 1 with either pIXY 321 or the combination of rIL-3 plus rGM-CSF led to modest but significant increases (e.g., 30 to 75%) in the number of CFU-GM, compared to administration of growth factors alone. The degree of bryostatin 1-induced potentiation, however, was considerably less than that previously observed in the case of cells exposed to either rIL-3 or rGM-CSF, where increases of 100 to 150% were regularly noted. While at least 50% of day-14 CFU-GM stimulated by either pIXY 321 or the combination of rIL-3 plus rGM-CSF were of the pure or mixed eosinophilic variety, coadministration of bryostatin 1 resulted in a dramatic inhibition of eosinophilic colonies and a corresponding increase in pure and mixed neutrophil and macrophage colonies. Although coadministration of recombinant granulocyte colony-stimulating factor (rG-CSF) or recombinant colony-stimulating factor-1 (rCSF-1) mimicked the capacity of bryostatin 1 to increase the total number of pIXY 321-induced day-14 CFU-GM, these growth factors, unlike bryostatin 1, were not capable of inhibiting eosinophilic colony formation. Furthermore, whereas addition of neutralizing antibodies to G-CSF or CSF-1 blocked the capacity of these growth factors to potentiate colony formation in the presence of pIXY 321, it did not abrogate the effect of bryostatin 1 on progenitor cell growth or lineage commitment. Finally, in contrast to its effects on committed myeloid progenitors, bryostatin 1 did not increase the growth of erythroid (burst-forming units-erythroid [BFU-E]) and multipotent (multipotent colony-forming units [CFU-GEMM]) progenitors stimulated by pIXY 321, but instead inhibited colony formation at higher concentrations (e.g., 10 to 100 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of the activity of a human granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein (pIXY 321) by the macrocyclic lactone protein kinase C activator bryostatin 1. 768 3

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