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)

Treatment of normal primary human keratinocytes with phorbol 12-myristate 13-acetate (PMA) or phorbol 12-13 dibutyrate (PDBu) (100 ng/ml, 6-40 h) followed by two-dimensional (2-D) gel electrophoresis (isoelectric focusing) and microsequencing identified three polypeptides (phorbolin 1, M(r) = 19.9 kDa; phorbolin 2, M(r) = 19.7 kDa; and interleukin-1 (IL-1) receptor antagonist, IL-1ra, M(r) = 19.5 kDa) that are upregulated eight times or more by the phorbol esters and that are highly expressed in noncultured psoriatic keratinocytes. The response was not elicited by other effectors tested including second messengers (Bt2cAMP, Bt2cGMP), cytokines (basic fibroblast growth factor, transforming growth factor-alpha, IGF-II, tumor necrosis factor-alpha, and -beta, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-6, IL-7, IL-8, interferon-alpha, and -gamma), and other substances (Ca++, dexametasone, retinoic acid, lipopolysaccharides) and it was partially reversed by staurosporine, a strong inhibitor of protein kinase C. The results are taken to imply that the protein kinase C signaling pathway may be altered in psoriatic keratinocytes.
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PMID:Evidence for an altered protein kinase C (PKC) signaling pathway in psoriasis. 840 24

Human peripheral blood natural killer (NK) cells (CD56+, CD16+, CD3 epsilon- lymphocytes) express CD69 after their stimulation by interleukin-2 (IL-2) or interferon-alpha (IFN-alpha). This activation antigen represents a triggering surface molecule in NK cell clones as its stimulation triggers the cytolytic machinery of these cells. However, the mechanisms regulating the expression of CD69 in NK cells are unknown despite the functional relevance of CD69 in NK cell activation. Thus, we have analyzed the role of protein kinase C (PKC) and protein tyrosine kinases (PTK) in the expression of CD69 on purified NK cells activated by IL-2, IFN-alpha, anti Fc gamma RIII (CD16) monoclonal antibodies or by K562 target cells. We found that CD69 is induced on NK cells not only by IL-2 and IFN-alpha but also by activation of the CD16 pathway, the interaction with NK target cells and the direct activation of PKC by phorbol 12-myristate 13-acetate (PMA), indicating that CD69 induction is associated to different NK activation pathways. The treatment with the PKC inhibitor staurosporine abolished the induction of CD69 induced by PMA or K562. However, it did not significantly affect CD69 induction by IL-2, IFN-alpha or CD16 cross-linking. This demonstrates that whereas PKC can play a central role in the regulation of CD69 expression in some instances (response to K562 cells or PMA), it does not participate in others (response to IL-2, IFN-alpha or anti CD16 monoclonal antibodies). On the other hand genistein, a competitive inhibitor of PTK enzymes, blocked the expression of CD69 induced by activation of NK cells via IL-2 or IFN-alpha receptors, CD16 and K562 receptor(s), indicating that stimulation of PTK is a common step in the signal transduction events leading to the induction of CD69 antigens after the activation of NK cells via these receptors.
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PMID:Regulation of CD69 expression on human natural killer cells: differential involvement of protein kinase C and protein tyrosine kinases. 847

Herpes simplex virus 1 (HSV-1) is able to induce interferon-alpha production by natural IFN-alpha-producing cells. In this study, signal transduction in this process was examined. It was found that sequestering of calcium by EGTA abolished IFN-alpha induction by HSV-infected cells. Stimulation of human PBMC by HSV-1-infected fibroblasts resulted in the production of inositol triphosphate (InsP3) and tyrosine phosphorylation of cellular proteins. The protein kinase C inhibitor, H7, and the tyrosine kinase inhibitor, herbimycin A, were able to suppress IFN-alpha gene expression as determined by IFN bioassay and RT-PCR. An IFN-alpha-specific ELISpot assay revealed that herbimycin A and H7 remarkably decreased the number of IFN-alpha-producing cells. PMA or calcium ionophore A23187 alone did not increase IFN-alpha production. However, PMA in conjugation with ionophores increased IFN-alpha production as early as 2 h. HA1004 and 2',5'-dideoxyadenosine, which are potent inhibitors of PKA pathway, had no effect on IFN-alpha production. In contrast, BrcAMP, a specific PKA activator, inhibited the IFN-alpha secretion and number of IFN-alpha-producing cells and to a lesser extent reduced the level of IFN-alpha mRNA. Our results indicate that protein kinase C, tyrosine kinases, and protein kinase A are involved in the regulation of IFN-alpha production in response to HSV-1.
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PMID:Role of tyrosine kinases, protein kinase C, and protein kinase A in the regulation of interferon-alpha production induced by herpes simplex virus type 1. 874 63

Induction of the p40/46 and p69/71 isoforms of the 2',5'-oligoadenylate (2-5A) synthetase by interferon-alpha (IFN-alpha) is variable among six different Burkitt lymphoma cell lines with Ramos cells expressing among the highest levels of these enzymes. Inhibitors of protein kinase C (PKC) block induction of mRNAs encoding both isoforms; however, induction of the p69/71 isoform is more sensitive to these inhibitors. Down-regulation of PKC by prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) also blocks induction of 2-5A synthetase mRNAs and decreases both constitutive and IFN-alpha-induced enzymatic activity. Cotreatment of cells with TPA and IFN-alpha increases induction of 2-5A synthetase mRNAs above that seen in cells treated with IFN-alpha alone. IFN-alpha does not directly activate PKC-alpha or PKC-delta, the two most abundant PKC isoforms present in Ramos cells, suggesting that PKC activation by another signaling pathway is necessary for maximal induction of 2-5A synthetases by IFN-alpha.
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PMID:Protein kinase C is required for induction of 2',5'-oligoadenylate synthetases. 926 Aug 91

This study was done to determine if the production and metabolism of reactive oxygen species from human neutrophils were modulated by the treatment of interferon-alpha (IFN-alpha). Luminol-dependent Chemiluminescence (LmCL) responses were inhibited by a high concentration of IFN-alpha (more than 1 x 10(4) IU/ml) when opsonized zymosan (OZ) and phorbol 12-myristate 13-acetate (PMA) were used as stimulants. However, these responses were increased by 1 x 10(3) IU/ml of IFN-alpha with Ca(2+)-ionophore A23187 stimulation. Lucigenin-dependent Chemiluminescence (LgCL) responses were inhibited by all concentrations. These findings suggest the possibility that IFN-alpha inhibits activation of protein kinase C (PKC), whereas the resulting effect might be due to the inhibition of myeloperoxidese (MPO) degranulation. Preincubation of human neutrophils with IFN-alpha for 30, 60 or 120 minutes and subsequent stimulation with OZ, PMA and Ca(2+)-ionophore A23187 caused an increase LgCL responses, while inhibiting LmCL responses. These findings suggest that preincubation of human neutrophils with a high concentration of IFN-alpha might enhance the NADPH-oxidase activity, although a relative increase of LgCL was due to the inhibition MPO degranulation.
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PMID:[The effects of interferon-alpha on oxygen radical production by human neutrophils]. 991 91

We examined the effects of interferon-alpha on the ATP-sensitive K+ current (IK,ATP) in rabbit ventricular cells using the patch-clamp technique. IK,ATP was induced by NaCN. Whole-cell experiments indicated that interferon-alpha (5 x 10(2) - 2.4 x 10(4) U/ml) inhibited IK,ATP in a concentration-dependent manner (60.7+/-7.5% with 2.4 x 10(4) U/ml). In cell-attached configuration, interferon-alpha (2.4 x 10(4) U/ml) applied to the external solution also inhibited the activity of the single ATP-sensitive K+ (KATP) channel by 56.0+/-5.8% without affecting the single channel conductance. The inhibitory effect of IK,ATP by interferon-alpha was blocked by genistein and herbimycin A, tyrosine kinase inhibitors, but was not affected by N-(2-metylpiperazyl)-5-isoquinolinesulfoamide (H-7), an inhibitor of protein kinase C and cAMP-dependent protein kinase. These findings suggest that interferon-alpha inhibits the cardiac KATP channel through the activation of tyrosine kinase. The tyrosine kinase-mediated inhibition of IK,ATP by cytokines may aggravate cell damage during myocardial ischemia.
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PMID:Tyrosine kinase-dependent modulation by interferon-alpha of the ATP-sensitive K+ current in rabbit ventricular myocytes. 1006 79

Prognosis of advanced, unresectable pancreatic adenocarcinoma remains dismal and has not significantly improved over the past 20 years. In a broad panel of preclinical experimental settings we have therefore evaluated the effects of retinoids on human pancreatic carcinoma cells in vitro and in vivo. We found that retinoid treatment results in inhibition of growth, induction of cellular differentiation and decreased adhesion to certain components of the extracellular matrix, all features compatible with a "less malignant" phenotype. Furthermore, retinoids act synergistically antiproliferative when combined with interferon-alpha. Using transient and stable genetic transfer studies we were able to identify two retinoid receptor subtypes responsible for mediating the growth inhibitory effects as well as retinoid sensitivity. In addition we observed a crucial functional interplay between the retinoid signalling pathway and the expression of a distinct protein kinase C isoenzyme, which determines the direction of the growth regulatory effects of retinoids. Based on these encouraging preclinical results we initiated a phase II clinical trial in which patients with advanced pancreatic carcinoma were treated with retinoic acid in combination with interferon-alpha. This therapeutic regimen was well tolerated and resulted in prolonged stable disease in approximately two thirds of the patients. In summary, these studies suggest that retinoids might be beneficial in the treatment of advanced pancreatic carcinoma patients based on their pleiotropic effects on tumor cell biology.
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PMID:Retinoids in pancreatic cancer. 1043 21

Induction of interferon-alpha (IFNalpha) gene expression in virus-infected cells requires phosphorylation-induced activation of the transcription factors IRF3 and IRF7. However, the kinase(s) that targets these proteins has not been identified. Using a combined pharmacological and genetic approach, we found that none of the kinases tested was responsible for IRF phosphorylation in cells infected with Newcastle disease virus (NDV). Although the broad-spectrum kinase inhibitor staurosporine potently blocked IRF3 and -7 phosphorylation, inhibitors for protein kinase C, protein kinase A, MEK, SAPK, IKK, and protein kinase R (PKR) were without effect. Both IkappaB kinase and PKR have been implicated in IFN induction, but cells genetically deficient in IkappaB kinase, PKR, or the PKR-related genes PERK, IRE1, or GCN2 retained the ability to phosphorylate IRF7 and induce IFNalpha. Interestingly, PKR mutant cells were defective for response to double-stranded (ds) RNA but not to virus infection, suggesting that dsRNA is not the only activating viral component. Consistent with this notion, protein synthesis was required for IRF7 phosphorylation in virus-infected cells, and the kinetics of phosphorylation and viral protein production were similar. Despite evidence for a lack of involvement of dsRNA and PKR, vaccinia virus E3L protein, a dsRNA-binding protein capable of inhibiting PKR, was an effective IRF3 and -7 phosphorylation inhibitor. These results suggest that a novel cellular protein that is activated by viral products in addition to dsRNA and is sensitive to E3L inhibition is responsible for IRF activation and reveal a novel mechanism for the anti-IFN effect of E3L distinct from its inhibition of PKR.
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PMID:IRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein. 1112 48

This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1alpha, IL-6, transforming growth factor (TGF)-alpha, conventional (c) protein kinase C (cPKC)-alpha, cPKC-betaII, phosphorylated (p)-PKC-alpha/betaII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the alpha subunit of farnesyl and geranylgeranyl transferase (FTalpha/GGTalpha), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bcl-2, TGF-beta1 latency-associated peptide (LAP), TGF-betaRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1alpha, cPKC-alpha, p-PKC-alpha/betaII, PDGFR-alpha, p-JNK, Ki-67, and bcl-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC-alpha and PDGFR-alpha signaling and anti-apoptotic bcl-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-alpha, rapamycin, ciprofloxacin, and STI571.
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PMID:Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. 1281 16

We recently demonstrated that IFNaR2, a subunit of the interferon receptor, can be proteolytically cleaved in response to interferon-alpha and other activators of protein kinase C. Cleavage occurs at multiple sites, via a mechanism similar to that employed by Notch and the Alzheimer's precursor protein, and releases the intracellular domain (ICD). In this study, we demonstrate that the IFNaR2 ICD, when fused to the yeast Gal4 DNA binding domain (Gal4DBD) selectively modulates transcription of four different promoters under the control of Gal4 upstream activating sequences. We previously showed that Stat2 binds constitutively to the ICD of IFNaR2, in a manner that is independent of tyrosine phosphorylation. Here, we show that ICD transcriptional modulation is dependent upon the carboxyl-terminal transactivation domain of Stat2. Specifically, complementing Stat2 deficient cells with wild-type Stat2 restored the ICD-mediated transcriptional effects while complementation with a mutant form of Stat2 lacking the transcriptional activation domain (TAD) did not. In addition, mutation of the Stat2 binding site on the ICD reduced the transcriptional activity of the Gal4DBD-ICD. Finally, we demonstrate that the activity of Jak1, a tyrosine kinase also known to bind to IFNaR2, is required for ICD-mediated transcriptional effects.
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PMID:Intracellular domain of the IFNaR2 interferon receptor subunit mediates transcription via Stat2. 1571 16


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