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)

Human HeLa cells and murine L(S) cells are highly sensitive to the cytocidal activity of tumor necrosis factor (TNF) when simultaneously treated with the inhibitor of protein synthesis cycloheximide. This cytocidal activity of TNF was inhibited up to 90% in both cell lines after a 15-60-min pretreatment with 3-10 ng/ml of phorbol 12-myristate 13-acetate (PMA). This inhibition was long lasting for HeLa cells but transient for L(S) cells. The protection afforded by PMA was most effective when the cells were pretreated with this phorbol ester, but it decreased when PMA was added together with TNF or after TNF addition. This finding suggested that PMA interfered with one of the early steps in the mechanism of action of TNF. A pretreatment with the calcium ionophore A23187 also reduced the cytocidal activity of TNF in both HeLa and L(S) cells to about the same extent. Treatment of these cells with either PMA or A23187 significantly decreased the binding of 125I-TNF to cell surface receptors. This decrease paralleled the time course and dose-response of the inhibition of cytocidal activity. In addition, treatment of HeLa cells with 1-oleyl-2-acetyl-glycerol (OAG) also induced a rapid loss of TNF binding capacity. Since OAG, PMA, and A23187 are all activators of protein kinase C (Ca2+/phospholipid-dependent enzyme), these results suggest that this kinase is involved in modulation of TNF sensitivity. Furthermore, depletion or inhibition of protein kinase C antagonized PMA-induced effects on TNF cytotoxicity and binding to receptors. Internalization of bound TNF was not significantly affected by PMA treatment, and Scatchard analysis of binding data indicated that PMA decreased TNF receptor binding affinity rather than the number of TNF-binding sites. These findings suggest that protein kinase C may have a physiological role in mediating TNF sensitivity.
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PMID:Tumor necrosis factor receptors and cytocidal activity are down-regulated by activators of protein kinase C. 283 10

Although tumor necrosis factor (TNF) and interleukin 1 (IL-1) affect many cell functions, the molecular mechanisms of TNF and IL-1 action are not understood. Our present study shows that exposure of human FS-4 fibroblasts to TNF or IL-1 caused a rapid accumulation of intracellular cAMP and an increase in protein kinase activity. Intracellular cAMP levels peaked 3-5 min after the addition of TNF or IL-1 and returned to basal level by 15 min. Increased phosphorylation of histone HII-B protein was demonstrated with extracts prepared from TNF- or IL-1-treated cells, suggesting an increase in cAMP-dependent protein kinase activity. No evidence was obtained for protein kinase C activation in TNF-treated FS-4 cells. TNF, IL-1, and forskolin all stimulated interleukin 6 (IL-6) mRNA levels in FS-4 cells. The protein kinase inhibitor H-8, inhibiting preferentially cAMP-dependent kinase activity, reduced forskolin-stimulated IL-6 mRNA induction more strongly than TNF- or IL-1-driven IL-6 mRNA induction. These results suggest that activation of cAMP-dependent protein kinase by TNF and IL-1 is important in some actions of these cytokines. In addition, our data on IL-6 induction by TNF and IL-1 suggest that other, yet unidentified, signal transduction mechanisms contribute to TNF and IL-1 actions on gene expression in human fibroblasts.
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PMID:Enhancement of cAMP levels and of protein kinase activity by tumor necrosis factor and interleukin 1 in human fibroblasts: role in the induction of interleukin 6. 284 90

Prior exposure of granulocytes to inflammatory mediators such as chemotactic factors, colony-stimulating factors and tumor necrosis factor primes the cells for enhanced activity of the respiratory burst, which appears not only to play an essential role in the increased host-defenses against invading microorganisms but also to be responsible for tissue damage at the inflammatory sites. The molecular basis for this priming is presently under investigation. Changes in one or more of the signal transduction events may lead to more efficient stimulation of the NADPH oxidase responsible for the respiratory burst. The mechanisms of priming appear to be different according to the priming stimuli: the chemotactic peptide and the Ca2+ ionophore may prime the cells by causing an increase in cytoplasmic free Ca2+; phorbol esters by activating protein kinase C; and colony-stimulating factors and tumor necrosis factor by activating the distinct mechanism, which is independent of an increase in cytoplasmic free Ca2+ and activation of protein kinase C.
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PMID:The respiratory burst of granulocytes: modulation by inflammatory mediators and its mechanism. 307 51

The expression in human fibroblasts of the beta 2-interferon (IFN-beta 2) gene, which is now recognized to be identical to the gene encoding B-cell differentiation factor BSF-2, is enhanced by several cytokines that affect cell growth (tumor necrosis factor, interleukin 1, platelet-derived growth factor, and beta 1-interferon). We have examined the possibility that IFN-beta 2 gene expression is regulated through activation, by diacylglycerol, of the protein kinase C pathway. The synthetic diacylglycerols 1,2-dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol strongly enhanced IFN-beta 2, but not IFN-beta 1, gene expression in human fibroblasts (FS-4 strain). An increase in IFN-beta 2 mRNA level was detected within 15 min after addition of diC8 (290 microM) to FS-4 cells and was maximal approximately 20 hr later. An increase in IFN-beta 2 gene transcription was detected within 5 min of addition of diC8, and the rate of transcription was near-maximal by 15-30 min. The enhancement of IFN-beta 2 gene expression by diC8, interleukin 1, or tumor necrosis factor was not prevented by H8, a preferential inhibitor of cAMP- and cGMP-dependent protein kinases, but was blocked by H7, an inhibitor of protein kinase C as well as of cyclic nucleotide-dependent protein kinases. diC8 was found to protect FS-4 cells from the cytopathic effect of vesicular stomatitis virus; this protection was blocked by polyclonal or monoclonal antibodies that neutralize IFN-beta, suggesting that the antiviral effect was due to the secretion of IFN-beta 2 by the diC8-treated fibroblasts. The calcium ionophore A23187 (1-10 microM) also elicited an increase in the level of IFN-beta 2 mRNA in FS-4 fibroblasts; appropriate combinations of A23187 and diC8 had at least an additive effect in enhancing IFN-beta 2 mRNA levels. These results show that protein kinase C-activating or [Ca2+]-elevating agents rapidly increase the expression of the IFN-beta 2 gene in human fibroblasts.
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PMID:Rapid enhancement of beta 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. 310 77

We studied the effect of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma), alone and in combination, on the expression of chemotactic peptide receptors, stimulus-induced actin polymerization, hydrogen peroxide production (H2O2), and expression of nonspecific esterase (NSE) positivity in human promyelocytic leukemic cell line HL-60. These parameters were analyzed following a five-day culture with the cytokines. Chemotactic peptide receptor expression was studied using the fluoresceinated hexapeptide, formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine and flow cytometry. Actin polymerization, an important event required for chemotaxis and phagocytosis, was studied using NBD-phallacidin labeling, following stimulation with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA). TNF increased the expression of chemotactic peptide receptors in a dose-dependent fashion, and there was good correlation between the receptor expression, stimulus-induced actin polymerization, H2O2 production, and NSE positivity. IFN-gamma was less potent in inducing all the parameters studied but exerted a positive cooperative effect when combined with TNF. IFN-gamma at high concentrations induced chemotactic peptide receptors comparable in magnitude to that seen with TNF but failed to prime these cells to undergo actin polymerization in response to FMLP or PMA. Undifferentiated HL-60 cells showed a decrease in F-actin content on stimulation with PMA. This suggests that protein kinase C might have a negative regulatory role in stimulus-induced actin polymerization. The observations reported here indicate that appropriate combinations of different inducing agents with different modes of action might be necessary to duplicate the functional abilities of mature phagocytic cells.
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PMID:Cooperative effect of tumor necrosis factor and gamma-interferon on chemotactic peptide receptor expression and stimulus-induced actin polymerization in HL-60 cells. 312 45

Phospholipase C (PLC)-mediated hydrolysis of membrane phospholipids results in the production of diacylglycerol, inositol phosphates, and choline metabolites. Inositol triphosphate increases calcium levels, while diacylglycerol activates protein kinase C. The present studies demonstrate that exogenous PLC generates inositol phosphates, releases choline metabolites, and activates protein kinase C in human HL-60 promyelocytic leukemia cells. PLC also induced monocytic differentiation of HL-60 cells as manifested by adherence, growth inhibition, and appearance of monocytic cell surface antigens. Furthermore, PLC treatment decreased c-myc mRNA levels and induced c-fos, c-fms, and tumor necrosis factor transcripts. The changes in gene expression induced by PLC are similar to those previously shown to be associated with phorbol ester-induced monocytic differentiation of HL-60 cells. Our results thus demonstrate that exogenous PLC activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation. PLC may therefore play a role in transducing signals from physiological inducers of monocytic differentiation.
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PMID:Phospholipase C activates protein kinase C and induces monocytic differentiation of HL-60 cells. 316

Mo3e is a protease-sensitive membrane antigen (p75,50) selectively expressed by human monocytic cells (monocytes and U-937 cells) stimulated in vitro by exposure to a variety of activating factors, including phorbol diester compounds, bacterial lipopolysaccharide (LPS), and muramyl dipeptide (MDP)(R.F. Todd et al., J. Immunol. 135, 3869, 1985). Here we report that primary and multiply-passaged cultures of HUVEC also express the Mo3e determinant after stimulation by phorbol myristate acetate (PMA) and related inducers of protein kinase C. As measured in a radioimmunoassay of anti-Mo3e antibody binding to monolayer cultures of HUVEC, unstimulated cells bore little if any Mo3e. After culture for 4-120 hr in medium containing PMA, 4 beta-phorbol dibutyrate, 4 beta-phorbol didecanoate, or mezerein (each at a concentration of 81 nM), or 1-oleoyl-2-acetoyl-sn-3-glycerol (1 mM), HUVEC were found to selectively express the Mo3e determinant. The magnitude of expression was dependent upon the concentration of the stimulus, maximal by 24 hr, and inhibited by cycloheximide. The combination of PMA and the calcium ionophore, ionomycin, had an additive or synergistic effect on HUVEC Mo3e expression. The biologically inactive phorbol compounds 4 beta-phorbol and 4 alpha-phorbol didecanoate failed to stimulate Mo3e expression. Also inactive as inducers of HUVEC Mo3e expression were crude lymphokine and monokine supernatants, recombinant human lymphokines (interferon-gamma and interleukin-2), recombinant human monokines (interleukin-1 and tumor necrosis factor), bacterial cell wall products including LPS and MDP, pharmacologic agents that increase intracellular cyclic adenosine monophosphate (prostaglandin E2, cholera toxin, theophylline, isoproterenol and isobutylmethylxanthine), lectins (Con A and PHA), and heparin. These results indicate that Mo3e is an inducible plasma membrane antigen of not only mononuclear phagocytes but also cultured HUVEC.
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PMID:Expression of Mo3e antigen by cultured human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA) and related pharmacological inducers of protein kinase C. 334 69

We tested the hypothesis that tumor necrosis factor-alpha (TNF) induces a peroxynitrite (ONOO-)-mediated depletion of glutathione via a protein kinase C (PKC)-dependent mechanism in pulmonary artery endothelial monolayers (PAEM). PAEM were incubated with TNF (1,000 U/ml) for 6 and 18 h. The PAEM were assayed for ONOO(-)-dependent changes in the concentration of luminol, free glutathione [Gfree; i.e., reduced glutathione and oxidized glutathione (GSSG)] and GSSG. TNF treatment decreased luminol and Gfree, and increased GSSG and GSSG/Gfree, compared with treatment with control media. The TNF-induced effects were prevented by co-incubation with the nitric oxide synthase inhibitors NG-monomethyl-L-arginine (1 mM), NG-nitro-L-arginine methyl ester (1 mM), or NG-nitro-L-arginine (1 mM). In addition, the TNF-induced effects were prevented by superoxide dismutase (10 U/ml), which removes O2-, and by urate (0.5 mM) and L-cysteine (3 mM), putative scavengers of ONOO-. The treatment of PAEM with the PKC activator phorbol 12-myristate 13-acetate (PMA, 1 microM) induced similar alterations in luminol and glutathione as TNF. TNF and PMA induced a protein of similar molecular weight (approximately 90 kDa) in the focal contact-rich fraction of PAEM lysate. TNF- and PMA-induced effects were prevented with the specific PKC inhibitor calphostin C (1 microM). The data indicate that TNF-induced PKC activation mediates ONOO- generation, which results in the oxidation and depletion of glutathione in PAEM.
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PMID:TNF-alpha induces peroxynitrite-mediated depletion of lung endothelial glutathione via protein kinase C. 748 29

Angiogenesis depends on cytokines and vascular cell adhesion events. Two cytokine-dependent pathways of angiogenesis were shown to exist and were defined by their dependency on distinct vascular cell integrins. In vivo angiogenesis in corneal or chorioallantoic membrane models induced by basic fibroblast growth factor or by tumor necrosis factor-alpha depended on alpha v beta 3, whereas angiogenesis initiated by vascular endothelial growth factor, transforming growth factor-alpha, or phorbol ester depended on alpha v beta 5. Antibody to each integrin selectively blocked one of these pathways, and a cyclic peptide antagonist of both integrins blocked angiogenesis stimulated by each cytokine tested. These pathways are further distinguished by their sensitivity to calphostin C, an inhibitor of protein kinase C that blocked angiogenesis potentiated by alpha v beta 5 but not by alpha v beta 3.
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PMID:Definition of two angiogenic pathways by distinct alpha v integrins. 749 98

Tissue distribution and expression on mitogen and virally stimulated lymphocytes render the ACT35 molecule a human lymphocyte activation antigen which as yet could not be clustered. Expression cloning of the ACT35 antigen from a pCDM8 library of the HUT-102 cell line revealed strong homology of the cDNA and its encoded protein sequence with the formerly described rat OX40 antigen. The 1.4-kb nucleotide sequence and the deduced 277-amino acid sequence of the single transmembrane protein were 65% and 63% identical, in human and in rat, respectively. Conservation included one N-linked glycosylation site and one protein kinase C phosphorylation site. When expressed in COS-1 cells, the cDNA presented properties comparable to the native ACT35 antigen and the rat OX40 molecule (relative molecular mass 48,000). Thus, the ACT35 protein corresponds to the hitherto unknown human OX40 antigen and is, therefore, another member of the tumor necrosis factor/nerve growth factor receptor (TNFR/NGFR) family. After applying fluorescence in situ hybridization, the human ACT35/OX40 gene could be mapped to chromosome band 1p36 and is, thus, linked to the genes for TNFR II and CD30.
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PMID:The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. 751 Feb 40


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