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)

Bryostatin 1 and the phorbol ester, phorbol myristate acetate (PMA), both bind to and activate protein kinase C (PKC) but exhibit divergent biological actions. Bryostatin 1 exerts variable effects on leukemic cell differentiation, and has been reported by some investigators to inhibit the proliferation of the monocytic leukemic cell line U937. In this study, we have compared the efficacy of bryostatin 1 and PMA with respect to U937 cell maturation, with a major emphasis on differential actions on the cell cycle arrest machinery. At equimolar concentrations (10 nM), PMA, in contrast to bryostatin 1, induced cellular differentiation of U937 cells, reflected by growth inhibition, increased plastic adhesion, and expression of the monocytic differentiation marker, CD11b. Consistent with these results, bryostatin 1 was less effective in inducing G0/G1 arrest and inhibiting cyclin-dependent kinase 2 (CDK2) activity. Bryostatin 1, unlike PMA, failed to induce expression of the cyclin-dependent kinase inhibitor (CDKI), p21CIP1/WAF1, and blocked the ability of PMA to induce this protein. Bryostatin 1 exposure resulted in increased expression of the CDKI p27KIP1 in these cells, although the kinetics differed from PMA. In addition, bryostatin 1 was less effective than PMA in dephosphorylating pRb, modifying E2F complexes, and downregulating c-Myc. Co-administration of bryostatin 1 with PMA antagonized the latter's differentiation-inducing capacity and anti-proliferative effects, actions that were accompanied by a reduction in PMA-mediated p21CIP1/WAF1 induction, CDK2 inhibition, pRb dephosphorylation, and c-Myc downregulation. Antagonistic effects of bryostatin 1 on PMA-related cell cycle events were mimicked by the specific PKC inhibitor GF109203X. Together, these studies indicate that bryostatin 1 is a considerably weaker stimulus than PMA for U937 cell differentiation, and raise the possibility that this deficiency arises from its failure to induce p21CIP1/WAF1 and trigger cell cycle arrest.
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PMID:Divergent effects of bryostatin 1 and phorbol myristate acetate on cell cycle arrest and maturation in human myelomonocytic leukemia cells (U937). 961 91

Platelets, activated by various agonists, produce microparticles (MP) from the plasma membrane, which are released into the extracellular space. Although the mechanism of MP formation has been clarified, their biological importance remains ill defined. We have recently shown that platelet-derived MP influence platelet and endothelial cell function. In this study, we have further examined the mechanism of cellular activation by platelet MP. To address the possibility that they may influence monocyte-endothelial interactions, we used an in vitro assay to examine their effects on the adhesion of monocytes to human umbilical vein endothelial cells (HUVEC). Platelet MP increased the adhesion of monocytes to HUVEC in a time- and dose-dependent manner. Maximal adhesion of monocytes to resting HUVEC was observed after 24 h of stimulation with MP. Similar kinetics were observed with U-937 (human promonocytic leukemia) cells, used as a model for the blood-borne monocyte. Maximal adhesion of resting monocytes to MP-stimulated HUVEC was observed after 5 h of stimulation with MP. The EC50s for MP-induced increases in HUVEC, monocyte, and U-937 cell adhesion is 8.74, 43.41, and 10.83 microg/ml of MP protein, respectively. The induction of monocyte-endothelial adhesion was mimicked by arachidonic acid isolated from MP. The observed increased cellular adhesiveness correlated with MP-induced upregulation of cell adhesion molecules. MP-stimulated HUVEC increased intracellular cell adhesion molecule-1 (ICAM-1) but not vascular cell adhesion molecule-1 (VCAM-1), P-, or E-selectin expression. Monocyte and U-937 lymphocyte function-associated antigen-1 (CD11a/CD18) and macrophage antigen-1 (CD11b/ CD18, alpham/beta2) were both upregulated upon MP stimulation, but an increase in p150,95 (CD11c/CD18), very late antigen-1, or ICAM-1 expression was not observed. The functional importance of these changes was demonstrated with blocking antibodies. MP also induced the chemotaxis of U-937 cells in a dose-dependent manner with an EC50 of 4.40 microg/ml of MP protein. Similarly, arachidonic acid isolated from MP mimicked the chemotactic response. A role for PKC was implicated in both adhesion and chemotaxis. GF 109203X, a specific inhibitor of PKC, significantly reduced monocyte-endothelial adhesion, as well as U-937 chemotaxis. The demonstration that platelet MP may modulate important aspects of endothelial and monocyte function provides a novel mechanism by which platelets may interact with such cells in human atherosclerosis and inflammation.
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PMID:Modulation of monocyte-endothelial cell interactions by platelet microparticles. 964 67

The effects of three inducers of differentiation, phorbol myristate acetate (PMA), retinoic acid (RA) and interferon-gamma (IFN-gamma), on the temporal regulation of vitamin D receptor (VDR) expression in HL-60 cells were analyzed by Northern blotting and immunofluorescence assays. VDR, at the protein level, expressed by 81% of uninduced cells, was reduced to 57% after 48 h of PMA or 96 h of RA treatment, preceded by growth inhibition and cell differentiation, evaluated by CD11b expression. Sorted CD11b positive cells in G0/G1 phase exhibited 53% the VDR content of CD11b negative cells (distributed throughout the cell cycle). PMA also induced an increase in PKC beta and PKC alpha mRNA and protein. Simultaneous exposure to PMA and sphingosine blocked stimulation of CD11b and PKC expression without affecting growth arrest and VDR down regulation. Similar effects were observed during sphingosine treatment. In IFN-gamma differentiated cells, the proportion of cells in G0/G1 phase was unchanged and VDR protein was unaltered as compared to uninduced cells. Control cells in G0/G1 expressed less VDR than cells in S and G2/M phases (74% and 59% respectively). All results suggest that in HL-60 cells, reduction of VDR expression is related to growth inhibition rather than to the differentiation process.
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PMID:Expression of vitamin D receptor (VDR) in HL-60 cells is differentially regulated during the process of differentiation induced by phorbol ester, retinoic acid or interferon-gamma. 974 16

Although eosinophils have been implicated in immune responses to certain types of tumors, the mechanisms of anti-tumor activity by eosinophils are poorly understood. We show here that mouse eosinophils kill allogeneic MCA-38 colon adenocarcinoma cells in the absence of specific anti-body. Eosinophil adhesion to MCA-38 monolayers occurred within 15 min and plateaued at 90 min. Although mouse eosinophils express alphaL (CD11a), alphaM (CD11b), and alpha4 (CD49d) integrin chains, blocking antibody studies revealed that these molecules are not involved in eosinophil binding to MCA-38 cells. Adhesion was also fibronectin-independent. Binding was inhibited when eosinophils, but not MCA-38 cells, were pretreated with methyl 2,5-dihydroxycinnamate (MDHC), a selective inhibitor of protein tyrosine kinases, or 8-Br-cAMP-Na, a cell-permeable cyclic AMP analogue. Adhesion was unaffected by calphostin C, a specific inhibitor of protein kinase C, and wortmannin, a selective inhibitor of phosphatidylinositol 3-kinases.
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PMID:Adhesion of tumoricidal eosinophils to MCA-38 colon adenocarcinoma cells involves protein tyrosine kinase activation and is diminished by elevated cyclic AMP in the effector cell. 982 49

5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a metabolite of arachidonic acid formed by the oxidation of 5-hydroxy-6,8,11, 14-eicosatetraenoic acid by a highly specific dehydrogenase. 5-oxo-ETE is a chemoattractant for both neutrophils and eosinophils. Although it is not as effective as leukotriene B4 (LTB4) and platelet-activating factor (PAF) in stimulating neutrophil migration, we found that it is considerably more active than these and a variety of other lipid mediators as an eosinophil chemoattractant. Moreover, low concentrations of 5-oxo-ETE appear to enhance the responsiveness of these cells to PAF. The objectives of the current investigation were to identify rapid responses induced in eosinophils by 5-oxo-ETE that might be related to the infiltration of these cells into tissues. We found that 5-oxo-ETE is more effective than PAF and LTB4 in inducing both L-selectin shedding and actin polymerization in human eosinophils, whereas PAF is the most active of these mediators in stimulating calcium mobilization. The complementary effects of 5-oxo-ETE and PAF on actin polymerization and calcium mobilization may explain their synergistic effect on eosinophil migration. 5-oxo-ETE and PAF were equipotent in stimulating the surface expression of the beta2-integrin CD11b, but were slightly less potent than LTB4. 5-oxo-ETE- induced actin polymerization was subject to homologous but not heterologous desensitization. It was not prevented by incubation of eosinophils with inhibitors of protein kinase C (staurosporine), mitogen-activated protein kinase kinase (PD98059), or phosphatidylinositol-3-kinase (wortmannin). In conclusion, 5-oxo-ETE is a potent activator of human eosinophils and may be an important regulator of tissue infiltration of these cells.
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PMID:5-oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of L-selectin shedding, surface expression of CD11b, actin polymerization, and calcium mobilization in human eosinophils. 987 Sep 30

PU.1 is a transcription factor found in macrophages, B cells, neutrophils, and hemopoietic stem cells. In macrophages PU.1 regulates a number of genes, including c-fms, CD11b, CD18, and FcgammaR1b. Previously, in primary macrophages PU.1 binding to the sequence GAGGAA was found to be induced by treatment with bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Here we investigated the role of protein kinase C (pKC) in the induction of PU.1 binding in macrophages. We report that pharmacological activation of pKC increases PU.1 binding, while inactivation of pKC inhibits the increases in PU.1 binding by agents which activate pKC in macrophages (LPS and tumor necrosis factor-alpha), but not by an agent which does not activate pKC (IFN-gamma). pKC activation may therefore be one pathway by which PU.1 binding may be increased in primary macrophages.
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PMID:Protein kinase C activation increases binding of transcription factor PU.1 in murine tissue macrophages. 992 Jul 60

FcgammaRIIIb (CD16) is a glycosyl phosphatidylinositol (GPI)-anchored low-affinity IgG receptor, exclusively expressed on human neutrophils. FcgammaRIIIb associates with complement receptor 3 (CR3, Mac-1, CD11b/CD18), which may indirectly link FcgammaRIIIb to the actin cytoskeleton. Upon neutrophil activation, apoptosis, or chemotaxis, FcgammaRIIIb is shed from the cell surface. In all of these events, actin rearrangements play an important role. To establish a role for the actin cytoskeleton in the control of FcgammaRIIIb shedding, we treated human neutrophils with jasplakinolide, an actin-polymerizing peptide. We show that enhanced actin polymerization induces time- and dose-dependent shedding of FcgammaRIIIb. This effect was not restricted to FcgammaRIIIb, because the cell surface expression of CD43, CD44, and L-selectin was also downregulated after induction of actin polymerization. This actin-dependent pathway is staurosporine sensitive but does not appear to involve activation of PKC or CR3. These data show that the actin cytoskeleton can regulate protein ectodomain shedding from human neutrophils.
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PMID:Actin polymerization induces shedding of FcgammaRIIIb (CD16) from human neutrophils. 1004 51

Priming of human eosinophils is an essential event for the respiratory burst induced by serum-opsonized particles [serum-treated zymosan (STZ)]. In this study we have found that treatment of eosinophils with platelet-activating factor (PAF) leads to activation of phospholipase D. Inhibition of the formation of phospholipase D-derived products by ethanol resulted in about 90% inhibition of PAF-induced binding of fluorescent STZ particles to the cells, but only when ethanol was added to the cells before treatment with PAF. When ethanol was added after treatment with PAF, only a minor inhibition of the STZ binding and STZ-induced response was observed. These results indicate that phospholipase D-derived phosphatidic acid is involved in PAF priming, without having an effect on STZ stimulation. In the presence of propranolol, which inhibits phosphatidic acid-phosphatase activity, binding of STZ particles to human eosinophils induced by suboptimal concentrations of PAF was enhanced, indicating that phosphatidic acid and not diradylglyceride is the relevant molecule derived from phospholipase D activity. Addition of cell-permeant diC8-phosphatidic acid (DiC8-PA) to human eosinophils resulted in CD11b/CD18-dependent adhesion, both to STZ particles and fibronectin-coated wells, without significant upregulation of CD11b/CD18. The DiC8-PA-induced adhesion was not mediated via the fatty acid moiety, because other C8-lipids such as 1,2-diC8-phosphatidylcholine, 1-C8-monoacylglycerol or C8-ceramide were without effect. Activation of protein kinase C with PMA or 1,2-diC8-diacylglycerol did result in enhanced STZ binding. However, under these latter conditions upregulation of CD11b/CD18 was observed. Taken together, these results suggest that phospholipase D-derived PA is involved in changing the affinity of the CD11b/CD18 integrin for its ligands.
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PMID:Phospholipase D-derived phosphatidic acid is involved in the activation of the CD11b/CD18 integrin in human eosinophils. 1022 63

Cell adhesion mediated by the CD11/CD18 integrins and their ligands, the ICAMs, is required for many leukocyte functions. In resting cells the integrins are nonadhesive, but when activated they become adhesive for their ligands. Previous findings have shown that a peptide derived from the first Ig domain of ICAM-2 (P1) binds to LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) and activates leukocyte aggregation. Because its mechanism of action has remained poorly understood, we have now studied the peptide-induced ligand binding in detail. Here we show that P1 was able to induce CD11/CD18-dependent adhesion of human T lymphocytes to immobilized, purified ICAM-1, -2, and -3. The optimal peptide concentration was 150 micrograms/ml, whereas concentrations higher than 400 micrograms/ml did not have any stimulatory effect. The increase in adhesion was detectable within 10 min of treatment with the peptide; it was dependent on energy, divalent cations, temperature, and an intact cytoskeleton but was unaffected by protein kinase C and protein tyrosine kinase inhibitors. Peptide treatment resulted in strong stimulation of the binding of soluble, recombinant ICAMs to T lymphocytes, showing that the integrin affinity toward its ligands was increased. Importantly, soluble ICAM-2Fc was also able to induce T lymphocyte adhesion to purified ICAM-1, -2, and -3, and it was a more potent stimulatory molecule than ICAM-1Fc or ICAM-3Fc.
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PMID:ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity. 1035 78

We examined the production of CD11b, CD62L and H2O2 by human peripheral blood granulocytes after treatment with soluble proteins prepared from five different pressure-disrupted strains of Staphylococcus aureus (SaSP) by flow cytometory. Peripheral blood was treated with final SaSP concentrations of 0.05, 0.5 and 5.0 micrograms for 20 min at 37 degrees C. The ratio of CD11b positive granulocytes did not increase at concentrations from 0.05 to 5.0 micrograms, but fluorescence intensity showed about two and three-fold increase, respectively, at concentrations of 0.5 and 5.0 micrograms, in comparison with that of control cells. The ratio CD62L positive cells decreased as follows: 0.5 microgram, 53.8% and 5.0 micrograms, 19.0%, respectively, whereas the control value was 79.8%. Fluorescence intensity also decreased as follows: 0.5 microgram, 10.4 and 5.0 micrograms, 9.2, respectively, whereas the control value was 46.8. Slight induction of H2O2 was found at 5.0 micrograms concentration only. In addition, SaSP treatment granulocytes that stimulated with PMA (1 ng) increased H2O2 production. Thus, SaSP has no beneficial effect against H2O2 production by granulocytes. All of the SaSP preparations indicated similar results for the production of CD11b, CD62L and H2O2 by granulocytes. SaSP effects activation of granulocytes, and the activation may occur independently of protein kinase C.
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PMID:[Soluble proteins from Staphylococcus aureus can change expression of CD11b and CD62L, but not H2O2 production by human blood granulocytes]. 1035 90


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