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)

Vascular cell adhesion molecule-1 (VCAM-1) is expressed not only by cytokine-activated endothelium in the kidney, but also by nonvascular cells such as renal tubular epithelial cells (TEC) and mesangial cells (MC). VCAM-1 is upregulated in these cells by the cytokines TNF-alpha, IL-1, and IFN-gamma. We have examined herein the regulation of VCAM-1 expression in TEC and the role played by protein kinase C (PKC). Activation of PKC with phorbol myristate acetate (PMA) or mezerein upregulates VCAM-1 expression by TEC dose-dependently. Maximal stimulation occurs after 6 hr, and declines thereafter. Activation of the protein kinase A pathway with forskolin does not upregulate VCAM-1. The TNF-alpha- and PMA-stimulated VCAM-1 expression is inhibited by the PKC and PKA inhibitor staurosporine (STS). The TNF-alpha-stimulated VCAM-1 expression is also inhibited by the PKC-specific inhibitor calphostin C. Protein synthesis inhibition with cycloheximide (CHX) and blocking of transcription with actinomycin D (ACT D) also inhibits the TNF-alpha and PMA-stimulated upregulation of VCAM-1. The TNF-alpha induced increase in VCAM-1 mRNA levels is blocked with STS and ACT D, but is superinduced with CHX. Thus, the TNF-alpha stimulated renal tubular VCAM-1 expression may involve activation of PKC and is transcriptionally regulated.
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PMID:Regulation of cytokine-stimulated vascular cell adhesion molecule-1 expression in renal tubular epithelial cells. 767 55

We have previously demonstrated that HLA-DR molecule expression induced by IFN-gamma is associated with phosphatidylinositide turnover, activation of protein kinase C, and elevation of intracellular calcium. Because phosphorylation of phospholipase C-gamma 1 on tyrosine residues is known to be involved in the activation of phosphatidylinositide turnover, we investigated the role of tyrosine protein kinase (TPK) in the signal transduction for IFN-gamma-inducible DR molecule expression on T98G cells. The effects of three specific TPK inhibitors, genistein, herbimycin A, and tyrphostin, suggest that TPK is involved in the signal transduction. These inhibitors inhibited the IFN-gamma-inducible DR molecule expression in a dose-dependent manner. Being consistent with this, immunoblotting with an anti-phosphotyrosine mAb revealed that IFN-gamma induces a rapid increase in protein tyrosine phosphorylation. Genistein not only abrogated the IFN-gamma-induced enhancement of tyrosine phosphorylation, but also inhibited the IFN-gamma-induced production of inositol-4-5-triphosphate and the elevation of intracellular calcium. However, these three TPK inhibitors failed to inhibit the DR molecule expression induced by PMA and A23187. These findings suggest that the tyrosine phosphorylation is an early and critical event that precedes phosphatidylinositide turnover leading to activation of protein kinase C and elevation of intracellular calcium concentration during IFN-gamma-inducible DR molecule expression.
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PMID:Inhibition of tyrosine phosphorylation prevents IFN-gamma-induced HLA-DR molecule expression. 767 23

Steady-state levels of mRNAs that encode specific Fc gamma R and Ia antigen genes have been measured in macrophages treated with interferons (IFNs) to examine the induction of these markers at the molecular level. Our previous studies suggested requirement for protein kinase C (PKC) in the IFN induction of these macrophage surface markers, although a difference in PKC dependence was found between IFN-alpha/beta- and IFN-gamma-induced Fc gamma R expression. The protein kinase antagonist H7, used previously to distinguish between the surface induction of Fc gamma R by IFN-alpha/beta and IFN-gamma, also distinguishes between the IFN-alpha and IFN-gamma in the induction of Fc gamma RI mRNA and Fc gamma RI surface expression. Protein kinase inhibitors blocked the IFN-gamma induction of Ia mRNA in a manner similar to that reported previously for cell surface Ia expression. It is concluded that Fc gamma RI is induced by both IFN-alpha and IFN-gamma through distinct biochemical pathways, whereas IFN-gamma utilizes distinct pathways to induce the two macrophage activation markers, Ia antigen and Fc gamma RI.
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PMID:Multiple pathways of interferon-induced gene expression in murine macrophages. 768 67

Activation pathways inducing the expression of the interferon (IFN)-gamma gene in a cytotoxic T lymphocyte (CTL) clone were studied for their effects on transcription and on mRNA stability. IFN-gamma was secreted by the CTL clone in response to the Ca2+ ionophore ionomycin when used in conjunction with either protein kinase C (PKC)-activating phorbol 12-myristate 13-acetate (PMA) or with agents increasing cAMP, including prostaglandin E2. We describe that ionomycin induced IFN-gamma gene transcription, which was totally inhibited in the presence of cyclosporin A (CSA), an immunosuppressant forming a calcineurin-inhibiting complex with cyclophilin. Ionomycin did not, however, permit accumulation of IFN-gamma mRNA. Activation of PKC by PMA or of cAMP-dependent protein kinase through increase in cAMP had no transcription-inducing effect, either alone or in conjunction with ionomycin, as measured in run on assays of the IFN-gamma gene. When transcription of the IFN-gamma gene, initiated in the presence of ionomycin and an agent increasing intracellular cAMP, was inhibited by CSA in the absence of PKC or cAMP-dependent protein kinase activation, the IFN-gamma mRNA was rapidly degraded (half-life = 30 min). When either PKC was activated or intracellular cAMP was increased at the time of inhibition with CSA, a stabilizing effect was observed on IFN-gamma mRNA, which led to an increase in secreted IFN-gamma. These effects were selective, they did not affect the rate of transcription of the actin gene, nor the accumulation of actin mRNA. These results show that (i) post-transcriptional events can be critical for IFN-gamma expression in activated lymphocytes, and (ii) specific stabilization of IFN-gamma mRNA can be mediated by activation of two different protein kinases involved in T cell activation.
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PMID:Regulation of interferon-gamma mRNA in a cytolytic T cell clone: Ca(2+)-induced transcription followed by mRNA stabilization through activation of protein kinase C or increase in cAMP. 773 90

Taxol has been known to block cell division by stabilizing microtubules with promising anticancer activity. However, taxol has distinct cell cycle-independent effects. Recently, this novel drug has been shown to provide a second signal for murine macrophage activation to tumoricidal activity via L-arginine-dependent nitric oxide (NO) synthesis. To investigate the mechanism of taxol-induced NO synthesis, we evaluated the ability of protein kinase C (PKC) inhibitors such as staurosporine (STSN) or polymyxin B to block taxol-induced effects. Taxol alone had only a small effect, whereas taxol in combination with rIFN-gamma markedly increased NO synthesis in a dose-dependent manner. STSN and polymyxin B decreased NO synthesis, which had been induced by rIFN-gamma plus taxol. Furthermore, prolonged incubation of the cells with phorbol ester, which down-regulates PKC activity, abolished synergistic cooperative effect of taxol with rIFN-gamma on NO synthesis. Synergy between IFN-gamma and taxol was mainly dependent on taxol-induced TNF-alpha secretion because not only the increase of inducible NO synthase (iNOS) gene expression by rIFN-gamma plus taxol was associated with the increased expression of TNF-alpha gene but also taxol-induced NO production was decreased by the treatment of anti-murine TNF-alpha neutralizing Abs. STSN and polymyxin B potently inhibited taxol-induced TNF-alpha secretion and TNF-alpha gene expression as well as iNOS gene expression by rIFN-gamma plus taxol. However, rIFN-gamma plus TNF-alpha-induced NO synthesis was not blocked by STSN or polymyxin B. This result indicates that TNF-alpha-induced signaling for induction of NO synthesis is not dependent on PKC activation, and further suggests that the point at which TNF-alpha acts on the NO synthesis from rIFN-gamma-primed macrophages lies next to the point of PKC activation. In conclusion, the present results strongly suggest that the capacity of taxol to increase NO synthesis from rIFN-gamma-primed macrophages is the result of taxol-induced TNF-alpha secretion via the signal transduction pathway of PKC activation.
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PMID:Involvement of protein kinase C during taxol-induced activation of murine peritoneal macrophages. 775 87

Previous studies showed that murine bone marrow-derived macrophages (M phi) induced in vitro by IL-3 express cellular prostaglandin G/H synthase (PGHS)-1 but not PGHS-2. To induce PGHS-2 in this study, the M phi were primed further with IFN-gamma plus LPS. The expression of the PGHS isozymes was determined by cytometric analysis using Abs against PGHS-1 and PGHS-2. The expression of PGHS-2, but not PGHS-1, was dexamethasone-sensitive. To assess PGE2-releasing capacity, the primed M phi were triggered by challenge with calcium ionophore A23187, the protein kinase C (PKC) activator PMA, exogenous arachidonic acid, and 1.1-micron latex bead particles. Our results showed that the primed M phi expressed both isozymes and responded to all challenges used to release a substantial amount of PGE2 (> 10 ng PGE2/10(6) cells/ml), whereas the control unprimed M phi responded to A23187 and arachidonic acid but not to PMA or latex beads to release PGE2. However, the primed M phi did not release PGE2 when triggered with nonphagocytosable particles (> or = 40 microns) or when pretreated with cytochalasin D before they were challenged with 1.1-micron beads. Furthermore, staurosporine, a PKC inhibitor, did not inhibit the PGE2 release triggered by the beads. PMA-triggered PGE2 release by the primed M phi, in sharp contrast, was staurosporine-sensitive but cytochalasin D-resistant. Our data suggest that there are multiple or alternative pathways for triggering PGE2 synthesis and release distinctively associated with two PGH synthase isozymes. It is of special interest that the novel pathway triggered by interiorization of particles is associated with the expression of PGHS-2.
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PMID:Prostaglandin E2 release triggered by phagocytosis of latex particles. A distinct association with prostaglandin synthase isozymes in bone marrow macrophages. 787 56

We analyzed the expression of the dsRNA-dependent protein kinase (PKR) during the activation of murine macrophages to the tumoricidal state by LPS and/or IFNs. LPS induced PKR expression in a dose-dependent manner at levels that were comparable with those observed in response to IFNs. By using the PKR inhibitor 2-aminopurine (2-AP), we have shown that the pathways of macrophage tumoricidal activation elicited by LPS and IFN-alpha beta, but not by IFN-gamma, included a 2-AP-sensitive step. In fact, LPS- and IFN-alpha beta-induced activation was inhibited by 2-AP, whereas the activation by IFN-gamma was not affected by the presence of the inhibitor. 2-AP did not affect the activation of protein kinase C or protein kinase A in intact cells. In the presence of 2-AP the up-regulation of IFN-beta mRNA by LPS was specifically inhibited, whereas the expression of glyceraldehyde-3-phosphate dehydrogenase mRNA or the induction of PKR remained unchanged, thereby demonstrating that 2-AP inhibited selective macrophage genes. The differential sensitivity to 2-AP suggested that the expression of a functional PKR may be required for the macrophage tumoricidal response triggered by LPS and IFN-alpha beta but not IFN-gamma.
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PMID:Potential requirement of a functional double-stranded RNA-dependent protein kinase (PKR) for the tumoricidal activation of macrophages by lipopolysaccharide or IFN-alpha beta, but not IFN-gamma. 799 54

Astrocytes, when appropriately stimulated, produce a variety of cytokines including TNF-alpha. Production of TNF-alpha by astrocytes stimulated with Newcastle disease virus (NDV) is achieved by transcriptional activation and mRNA stabilization. A PKC-dependent pathway is responsible for a 10-fold increase in TNF-alpha mRNA stability by reducing poly(A) tail removal. The present study examined signal pathways induced by NDV in primary rat astrocytes that are responsible for TNF-alpha gene transcription as well as the possible source of kinase activity required for mRNA stabilization. Transcription of TNF-alpha gene in astrocytes stimulated by NDV or LPS and IFN-gamma was inhibited completely by the tyrosine kinase inhibitor herbimycin, and partially by a PKC inhibitor H7, as determined by nuclear run-on assay. HA-1004, a cyclic nucleotide-dependent kinase inhibitor, showed no effect. These results indicated that tyrosine kinase signaling pathways seemed to precede the activation of PKC in induction of TNF-alpha gene. Increase in tyrosine kinase activity in NDV-infected astrocytes was demonstrated by a two- to threefold increase in tyrosine phosphorylation of Pl-PLC gamma 1. Because astrocytes contain minimal Pl-PLC beta, and NDV-induced TNF-alpha mRNA was affected by pertussis toxin only modestly, Pl-PLC gamma 1 is likely the enzyme responsible for DAG generation and the PKC-dependent mRNA stabilization in response to NDV.
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PMID:Tyrosine kinase activation by Newcastle disease virus is required for TNF-alpha gene induction in astrocytes. 808 95

Intercellular adhesion molecule 1 (ICAM-1) is a major adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells including cancer cells regulated by various proinflammatory cytokines. Incubation of the human glioma cell line HS 683 and the neuroblastoma cell line SK-N-SH with 12-phorbol 13-myristic acid (PMA), retinoic acid, or gamma-interferon (IFN-gamma) strongly stimulates ICAM-1 expression. In the present study, we investigated the role of the protein kinase C (PKC)-mediated signal transduction pathway in this process. We found that IFN-gamma, but not retinoic acid, was able to induce activation and translocation of PKC after 60 min in a dose-dependent fashion, contrasting with the very rapid activation and translocation induced by PMA which occurred at 15 min. The PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride and staurosporine, as well as depletion of PKC by a 24-h treatment with 100 nM PMA, decreased the PMA-mediated stimulation but not the retinoic acid- or the IFN-gamma-mediated stimulation of ICAM-1 expression. On the contrary, they rather stimulated ICAM-1 expression. Furthermore, this stimulation was additive with retinoic acid and IFN-gamma. A 24-h incubation in the presence of retinoic acid or IFN-gamma strongly inhibited activation and translocation of PKC by PMA. These results suggest that although PMA-induced ICAM-1 expression is PKC dependent on HS 683 and SK-N-SH cells, the stimulation of ICAM-1 expression by retinoic acid and by IFN-gamma may be due to PKC inactivation at longer time points (24 h), as mimicked by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, staurosporine, or PKC depletion by high doses of PMA.
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PMID:Transduction of retinoic acid and gamma-interferon signal for intercellular adhesion molecule-1 expression on human tumor cell lines: evidence for the late-acting involvement of protein kinase C inactivation. 809 32

The effects of CGP 41251, a specific inhibitor of protein kinase C (PKC), its inactive derivative CGP 42700, and of staurosporine have been analyzed in vitro on T lymphocyte functions. The proliferation of fresh human peripheral blood lymphocytes stimulated with antigen (PPD) or anti-CD3 mAb was strongly inhibited by both staurosporine (IC50 < 0.01 microM) and CGP 41251 (IC50 = 0.092 microM) but not by the PKC inactive compound CGP 42700 (IC50 > 10 microM). Antigen-specific activation and proliferation of mouse lymph node T cells was inhibited by staurosporine and CGP 41251 with IC50 values of 0.008 and 0.05 microM, respectively. The inactive derivative caused 50% inhibition in this mouse T cell assay only at concentrations of 25 microM. In order to evaluate possible differential effects of PKC inhibitors on CD4+ T cell subsets, murine T helper cell type 1 (Th1) and type 2 (Th2) clones were used. The KLH-specific clone 9/6 secretes IL-2 and IFN-gamma (Th1), whereas clone 9A/B does not secrete these lymphokines but secretes IL-4 and IL-5 (Th2). It was found that CGP 41251 inhibited antigen-induced proliferation of both Th1 and Th2 equally well with an IC50 of 0.02 microM. Furthermore, CGP 41251 inhibited the IL-2 or IL-2 and IL-4-mediated growth of Th1 and Th2 cells (IC50, 0.08 and 0.02 microM, respectively). Moreover, CGP 41251, but not CGP 42700, inhibited antigen-specific killing of target cells by Th1 clones (IC50 = 0.2 microM), a phenomenon which does not require cell proliferation. When Th1 cells were preincubated with the compound, washed, and rested for 24 hr, they killed the target cells, whereas killing by similarly preincubated, washed, but not rested Th1 cells was inhibited. Thus, the inhibitory effect of CGP 41251 is reversible and excludes the possibility of inhibition due to toxicity at the IC50 dose given. The comparison of CGP 41251 and staurosporine showed that although CGP 41251 has lower activity, it is more specific and much less toxic than staurosporine. Thus, CGP 41251 is more suitable for PKC studies.
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PMID:Effects of a new protein kinase C inhibitor CGP 41251 on T cell functions: inhibition of activation, growth, and target cell killing. 810 85


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