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)

We investigated the positive and negative effects of IFN-gamma, PMA, dibutyryl cAMP (Bt2cAMP), dexamethasone and transforming growth factor-beta (TGF-beta) on Fc gamma R subtype expression and phagocytosis of a human monoblast cell line, U937. IFN-gamma increased and Bt2cAMP decreased Fc gamma RI expression determined by a mAb 32.2, whereas PMA and Bt2cAMP increased Fc gamma RII expression determined by a mAb IV-3. Phagocytosis was measured microscopically by counting ingested aggregated human IgG- or BSA-treated ox E (Eo'-IgG or Eo'-BSA). IFN-gamma increased the phagocytosis of Eo'-IgG but not that of Eo'-BSA, and PMA increased the phagocytosis of both Eo'-IgG and Eo'-BSA. Bt2cAMP decreased both basal and IFN-gamma- and PMA-augmented phagocytosis of U937 cells. Dexamethasone also inhibited both basal and IFN-gamma-augmented Fc gamma RI expression and PMA-augmented Fc gamma RII expression and phagocytosis, but did not affect IFN-gamma-augmented phagocytosis of Eo'-IgG. The augmentation of phagocytosis of Eo'-IgG by IFN-gamma thus seems to be due mainly to the increased internalizing process rather than to increased Fc gamma RI expression. TGF-beta slightly decreased Fc gamma R expression. In a study of the participation of protein kinase C (PK-C), it was found that H-7, a PK-C inhibitor, did not inhibit either IFN-gamma- or PMA-enhanced Fc gamma RI and Fc gamma RII expression, respectively, and 1-oleoyl-2-acetylglycerol and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide, both PK-C activators, did not show any apparent increase in Fc gamma R expression and phagocytosis. These results show that Fc gamma RI and Fc gamma RII expression on U937 cells is regulated by different mechanisms and that IFN-gamma and PMA play their roles in Fc gamma R expression and phagocytosis by different pathways. It is possible that cAMP but not PK-C plays an important role in the regulation of Fc gamma R expression and phagocytosis.
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PMID:Regulation of Fc gamma receptor expression and phagocytosis of a human monoblast cell line U937. Participation of cAMP and protein kinase C in the effects of IFN-gamma and phorbol ester. 255 78

The cross-linking of Fc receptors (FcR) on HL-60 cells inhibited the ability of recombinant IFN-gamma to induce HLA class II antigens. This appeared to be correlated with intracellular mRNA level. HL-60 lacked detectable HLA class II mRNA. IFN-gamma led to appearance of these transcripts, which were canceled by the cross-linking of FcR. Therefore, experiments were designed to investigate the intracellular signaling molecules regulating the appearance of HLA class II molecules or transcripts. The expression of HLA class II antigen induced by IFN-gamma was blocked by a calmodulin antagonist, W-7, but not by a protein kinase C (PKC) inhibitor, H-7. Furthermore, a direct activator of PKC, phorbol myristate acetate, was not able to induce the HLA class II antigen expression. These results suggest that IFN-gamma induces HLA class II antigens on HL-60 cells via a calcium-calmodulin pathway and not via a PKC pathway. Calmodulin is activated by a transient rise in the cytosolic free calcium. In fact, the measurement of calcium influx into HL-60 cells showed that a remarkable and time-dependent calcium accumulation was caused by IFN-gamma, and that depletion of Ca2+ from culture medium resulted in failure of IFN-gamma to induce class II antigen expression. Furthermore, calcium ionophore, A23187, by itself induced HLA class II antigen expression. These results suggest that IFN-gamma stimulates calcium influx and activates the calmodulin branch of the calcium messenger system, resulting in the induction of class II antigen expression on HL-60 cells. On the other hand, cross-linking of FcR elicited the accumulation of intracellular cAMP, which appeared to suppress the IFN-gamma-induced calcium influx, resulting in annulling HLA class II antigen-inducing activity of IFN-gamma. These intracellular events of HL-60 regulate the expression of HLA class II transcripts and molecules.
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PMID:Regulation of HLA class II antigen expression: intracellular signaling molecules responsible for the regulation by IFN-gamma and cross-linking of Fc receptors in HL-60 cells. 304 Aug 58

We have analyzed the mechanism of action of BSF-1 on class II gene expression in two murine pre-B cell lines that are at different stages of differentiation. In vitro transcription assays demonstrated that BSF-1 induced rapid transcription of class II genes within 1 hr by a mechanism that was independent of protein synthesis. Although cell surface expression of class II was detectable by 2 hr after induction and persisted for up to 96 hr after removal of BSF-1, levels of class II-specific mRNA and density of cell surface class II increased to a maximum between 24 and 72 hr after induction. Furthermore, prostaglandin E2 prevented the induction of class II gene expression by BSF-1. The effects of BSF-1 are unlikely to be mediated through calcium fluxes or activation of protein kinase C, since treatment with agents such as PMA and the calcium ionophore A23187 did not result in expression of class II molecules. Other lymphokines, such as IFN-gamma, IL 1, IL 2, and IL 3, did not affect class II gene expression in these two cell lines. These data provide further insight into the mechanisms by which class II gene expression is regulated in B cells.
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PMID:Regulation of class II gene expression: analysis in B cell stimulatory factor 1-inducible murine pre-B cell lines. 309 28

The functional and biochemical responses of macrophages derived from the A/J mouse strain to IFN-gamma have been studied. As compared to macrophages obtained from C57BL/6 strain mice, cells from mice of the A/J strain are deficient in their response to IFN-gamma for acquisition of tumoricidal competence. This deficiency was not due to reduced expression of surface receptors for IFN-gamma or to altered affinity of the receptor for its ligand. IFN-gamma recently has been shown to enhance the potential activity of protein kinase C (PKc) and to modulate the efflux of intracellular Ca2+ in macrophages from C57BL/6 mice. Neither of these two biochemical changes were induced in macrophages derived from A/J mice. Functional competence could, however, be pharmacologically induced in both C57BL/6- and A/J-derived macrophages by combined treatment with an ionophore plus phorbol myristic acetate, which increase intracellular Ca2+ and stimulate PKc, respectively. Although the exact nature of the deficit in A/J strain mice has not been defined, the present findings indicate that it lies between the expression of receptor and the modulation of PKc activity and Ca2+ levels. Furthermore, the data provide support for the notion that these molecular changes are important components of the stimulus-response coupling process in IFN-gamma-mediated activation of macrophages.
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PMID:Analysis of deficiencies in IFN-gamma-mediated priming for tumor cytotoxicity in peritoneal macrophages from A/J mice. 309 30

We investigated the effects of human interferon(IFN)-beta and -gamma on protein kinase C activity in human HEp-2 and KHm-14 tumor cells during IFN-induced inhibition of cell growth. Cytosolic protein kinase C activity in both cell lines was strikingly decreased following treatment with either IFN-beta or -gamma. In the particulate fraction, IFN-gamma decreased protein kinase C activity within 1 hr but it reappeared after 24 hr, whereas IFN-beta decreased the activity during the inhibition of cell growth. Furthermore, phorbol-12,13-dibutyrate(PDBu)-binding activity was altered in parallel with the changes in protein kinase C activity induced by the IFNs. In summary, we showed that IFN-beta and -gamma cause long-term modulation of protein kinase C activity in these cultured tumor cells.
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PMID:Modulation of protein kinase C activity during inhibition of tumor cell growth by IFN-beta and -gamma. 312 51

We investigated the role of protein kinase C (PK-C) in the activation of cytotoxic peritoneal murine macrophages (M phi) by IFN-gamma or by IFN-beta. Two potent inhibitors of PK-C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and retinal, were used. We found that both drugs inhibited in a dose-dependent manner the activation of cytotoxicity induced by IFN-beta, suggesting the requirement for intact PK-C activity in this process. In contrast, neither H-7 nor retinal inhibited the activation of cytotoxic M phi by IFN-gamma, indicating that IFN-gamma acts through a PK-C-independent pathway. The effectiveness of both drugs in inhibiting PK-C in intact M phi was evaluated by measuring the inhibition of induction of c-fos mRNA by L-alpha-1-oleoyl-2-acetoyl-sn-3-glycerol, a process that has been shown to be dependent on PK-C activation. We have found a strict correlation in the dose-dependent inhibition by both drugs of c-fos mRNA induction and activation of M phi by IFN-beta. These results indicate that different pathways of activation are triggered by IFN-gamma and IFN-beta, the former being independent from and the latter dependent on intact PK-C activity.
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PMID:Protein kinase C inhibitors block the activation of macrophages by IFN-beta but not by IFN-gamma. 312 52

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

Interleukin-2 (IL-2) is a regulatory peptide important for the growth and differentiation of antigen-specific T lymphocytes and large granular lymphocytes. Interaction of IL-2 with its specific receptor results in the promotion of S-phase progression as well as, in certain circumstances, the production and release of gamma-interferon (IFN-gamma). Although the binding of IL-2 with high-affinity specific receptors has been well characterized, the intracellular mechanisms by which this ligand-receptor interaction promotes growth and differentiation are unknown. Here, we present evidence that IL-2/receptor interaction produces a rapid and transient redistribution of protein kinase C (PK-C) from the cytosol to the plasma membrane. Phorbol myristate acetate (PMA) also induces PK-C transposition in an analogous manner, except that PMA-induced PK-C transposition to the plasma membrane is apparently protracted. As phorbol esters have been shown to mimic IL-2 in the regulation of cellular proliferation as well as IFN-gamma production, the activation of PK-C by either phorbol esters or IL-2/receptor interaction seems to have a crucial role in signal transduction elicited by these extracellular messengers.
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PMID:Interleukin-2 stimulates association of protein kinase C with plasma membrane. 315 20

We developed and applied a quantitative competitive polymerase chain reaction method to study the expression of various cytokine genes in Con A-stimulated murine splenocytes. This method relies on the use of competitive templates that differ from the target cytokine cDNA templates only by the introduction of a unique restriction endonuclease site in the center of each competitive template. After same-tube amplification using a single pair of oligonucleotide primers for both the target and competitive templates, restriction with the unique endonuclease yields 2 species that are readily resolved on agarose gel electrophoresis: full-length target and half-length competitor fragments. Using this method, we studied the time course and effects of CsA and rapamycin on IL-2, IFN-gamma, IL-4, and IL-10 gene expression following Con A stimulation. IL-2, IFN-gamma, and IL-10 share a common pattern of gene expression peaking at approximately 6 hr, while IL-4 gene expression peaks later, at approximately 20 hr. CsA very effectively inhibits expression of IL-2, IFN-gamma, and IL-4, but it inhibits IL-10 expression only 65%. Rapamycin inhibits IL-10 gene expression 100% and is less effective inhibiting the other cytokines. This pattern of inhibition is consistent with a calcium and protein kinase C independent pathway for IL-10 gene regulation and supports the notion that CsA and rapamycin may be used together to advantage.
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PMID:Quantitative comparison of rapamycin and cyclosporine effects on cytokine gene expression studied by reverse transcriptase-competitive polymerase chain reaction. 751 20

We have previously reported that CD7 expressed on resting human NK cells is a signal-transducing molecule, which upon ligation with mAb induces a rapid increase in cytoplasmic free calcium, secretion of IFN-gamma, and augmented NK activity against K562 targets. We now demonstrate that Ab-mediated clustering of CD7 molecules on NK cells results in enhanced phosphorylation on tyrosine residues of intracellular proteins of 60, 70, 80, 97, and 120 kDa. In the presence of genistein, a specific inhibitor of protein tyrosine kinase, the enhanced level of tyrosine phosphorylation was blocked, indicating that CD7 may induce signaling via activation of tyrosine kinases. Cross-linking of CD7 or CD16 molecules with primary and secondary Abs, as well as stimulation of NK cells with phorbol ester (PMA) or with calcium ionophore A23187 also induced beta 1 integrin-mediated adhesion of these cells to fibronectin (FN)-coated plastic surfaces. In contrast, cross-linking of CD2 expressed on the surface of NK cells had no significant effect on NK cell adhesion to FN. This adhesion was not associated with up-regulation of expression of alpha 4 beta 1 or alpha 5 beta 1 FN receptors on NK cells, but it required an intact cytoskeleton. The CD7-induced adhesion to FN was mediated by alpha 4 beta 1 and alpha 5 beta 1 integrins, as it was partially blocked by FN connective segment-1 peptide (EILDVPST), the alpha 4 beta 1-binding domain, as well as by RGD-containing peptides, the alpha 5 beta 1-binding domain, but not by EILEVPST or RGE control peptides. NK cell binding to FN was also partially inhibited by mAb to alpha 4, alpha 5, and beta 1 integrins. The mechanism by which cross-linking of CD7 or CD16 on NK cells induced adhesion to FN appeared to involve both protein tyrosine kinase and protein kinase C, because this adhesion was blocked in the presence of either genistein or a protein kinase C inhibitor, staurosporin. Our data demonstrate that signals transduced via triggering of either CD7 or CD16 molecules are involved in the regulation of the functional activity of beta 1 integrins on NK cells.
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PMID:Signaling via CD7 molecules on human NK cells. Induction of tyrosine phosphorylation and beta 1 integrin-mediated adhesion to fibronectin. 752 96


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