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 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

Flavone-8-acetic (FAA) acid is a potential chemotherapeutic agent that has demonstrated strong immunomodulatory activity in murine model systems. The immunomodulatory activity of this drug in murine systems has been linked to its ability to rapidly induce cytokine gene expression in vivo and in mouse splenocytes ex vivo. We have now developed a tissue culture model for studying the molecular basis of induction of cytokine expression by FAA. Using the mouse macrophage cell line, ANA-1, we can demonstrate the direct induction of interferon beta (IFN beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), and interferon response factor-1 (IRF-1) mRNA expression following treatment with FAA. Furthermore, the induction of the IFN beta mRNA can occur in the absence of new protein synthesis. Nuclear run-on experiments indicate that at least part of the induction of IFN beta, IL-6, and TNF alpha mRNA occurs at the transcriptional level while the increase in IRF-1 mRNA appears largely post-transcriptional or due to the production of IFN beta protein. Additionally, experiments using agents that interfere with second messengers demonstrate that activation of the protein kinase C pathway is possibly involved in FAA gene induction. The use of this tissue culture model system should lead to a more complete understanding of the mechanisms involved in FAA-induced gene expression and help determine why this drug is inactive on human cells.
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PMID:Induction of multiple cytokine gene expression and IRF-1 mRNA by flavone acetic acid in a murine macrophage cell line. 803 45

The signal pathways by which interferon-gamma (IFN-gamma) is able to up-regulate major histocompatibility complex (MHC) class I transcription were studied in two human hematopoietic tumor cell lines, K562 and Ramos. These studies suggest that the IFN-gamma signal is transduced via an H7- and staurosporine-sensitive kinase that is distinct from protein kinase C (PKC) and protein kinase A (PKA) in both cell types. Ramos cells appear to utilize an additional pathway involving double-stranded RNA-dependent protein kinase. PKC and possibly PKA appear to be involved in one or more intersecting pathways by which agonists of these kinases are able to act synergistically with IFN-gamma, but activation of these latter pathways is neither necessary nor sufficient for induction of MHC class I transcription. Modulation of G-protein- and Ca2+-calmodulin-associated pathways and arachidonic acid metabolism had no effect on constitutive or IFN-gamma-stimulated class I transcription. The class I stimulatory factor produced in response to IFN-gamma treatment appears to have a short t1/2. The identity of this factor is unknown, but is likely to be distinct from known mediators of IFN-stimulated transcription. Gene and cell-type specificity in the signal transduction pathways utilized by IFN-gamma implies that such pathways may be useful targets for experimental and therapeutic manipulation.
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PMID:Stimulation of MHC class I transcription by interferon-gamma involves a non-A, non-C kinase in addition to protein kinase C. 809 99

Both IFN-alpha/beta and IFN-gamma have recently been demonstrated to induce a rapid but transient activation of phospholipase A2 (PLA2) in BALB/c 3T3 fibroblasts and a human neuroblastoma cell line. We report that IFN-gamma induces the synthesis and prolonged activation of cytosolic phospholipase A2 (cPLA2) in a human bronchial epithelial cell line (BEAS 2B). Treatment of the cells with IFN-gamma (300 U/ml) increased the release of [3H]arachidonic acid (AA) from prelabeled cells with a maximal effect at 12 h after stimulation. The increased [3H]AA release was inhibited by the PLA2 inhibitor p-bromophenacyl bromide (10(-5) M). Calcium ionophore A23187 (10(-5) M) further increased the [3H]AA release from the IFN-gamma-treated cells. Subcellular enzyme activity assay revealed that IFN-gamma increased PLA2 activity in both the cytosol and membrane fractions with a translocation of the cPLA2 to cell membranes in a Ca(2+)-free cell lysing buffer. Treatment with IFN-gamma also induced the release of 15-HETE, an arachidonic acid metabolite. Immunoblot showed that IFN-gamma induced the synthesis of cPLA2 protein. Nuclear run-on assay demonstrated that IFN-gamma initiated cPLA2 gene transcription within 15 min, and this effect was sustained at 4 h and returned to near control level at 12 h. The cPLA2 mRNA level was assayed by reverse transcription and PCR. IFN-gamma was found to increase the cPLA2 mRNA after 2-24 h treatment. Furthermore, the IFN-gamma induced cPLA2 mRNA increase was blocked by inhibitors of protein kinase C and calcium/calmodulin-dependent protein kinases, suggesting the involvement of these protein kinases in IFN-gamma-induced gene expression of cPLA2. This study shows that IFN-gamma induces the synthesis and prolonged activation of cPLA2.
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PMID:Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. 811 94

IFNs are well characterized macrophage-activating agents. Their varied effects are largely mediated via the induction of many genes, whose products act in concert to induce macrophage differentiation. Homologous DNA sequences have been found upstream of the promoter in many of these IFN-inducible genes and bind a family of trans-acting proteins. Interferon consensus sequence binding protein (ICSBP) is one member of this family of interferon regulatory factors (IRF) and is structurally related within the DNA-binding domain to the other members, IRF-1, IRF-2, and ISGF3 gamma. ISCBP mRNA levels become elevated in response to IFN-gamma; however, little is known about the regulation of ICSBP expression at the protein level. In this study, anti-ICSBP peptide Abs were used to quantify and localize ICSBP in murine peritoneal exudate macrophages. Western blot analysis of cytoplasmic and nuclear extracts from treated and control cells revealed ICSBP to be induced by IFN-gamma and not by IFN-alpha and to exist primarily in the nucleus. The regulation of ICSBP induction by IFN-gamma was consistent with the characteristics found at the mRNA level; inhibition by IFN-alpha or glucocorticoids and the requirement for protein kinase C (as determined pharmacologically). The time course of IFN-gamma-induced ICSBP showed an induction of protein that required approximately 12 h to reach maximal levels. Induced ICSBP was relatively stable, exhibiting a half-life of approximately 48 h. Indirect immunofluorescence also demonstrated ICSBP to be an IFN-gamma-inducible protein that is strongly localized to the nucleus.
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PMID:Regulation of IFN-gamma-induced nuclear expression of IFN consensus sequence binding protein in murine peritoneal macrophages. 813 40

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. The etiology of the disease is still unknown. Activated T lymphocytes are considered essential in mediating the inflammatory process leading to demyelination in MS. They operate through a complex network of cytokines among which gamma interferon (gamma-IFN) plays a key role. Here we report that exposure to gamma-IFN of T lymphocytes from patients with MS activates, by a protein kinase C-mediated pathway, a previously undescribed gamma-IFN-activated Ca2+ influx, functionally coupled to the gamma-IFN receptor. The influx mainly expressed by CD4+ T lymphocytes, was found in 12 of 15 (80%) patients with clinically active MS and in 14 of 30 (46%) patients with stable MS. The influx was found in only 3 of 24 (12%) control patients and in none of the 15 healthy subjects studied. Our results document the appearance in MS lymphocytes of a gamma-IFN-activated, protein kinase C-dependent, Ca2+ influx that might be due to the expression of a new cation-specific plasmalemma channel. This finding suggests that at least part of gamma-IFN's contribution to the pathogenesis of MS is exerted through a Ca(2+)-dependent regulation of T lymphocyte activity.
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PMID:Gamma interferon activates a previously undescribed Ca2+ influx in T lymphocytes from patients with multiple sclerosis. 819 42

Murine macrophages respond to endotoxins by inducing a vast array of genes that play a major role in the host's response to infection and tumor growth. We have isolated and characterized a 1.8-kb cDNA, designated IRG2, from a cDNA library prepared from RNA isolated from the murine cell line, RAW 264.7, after bacterial LPS stimulation. The cDNA encodes a protein of 47 kDa that is the murine homologue of a small family of proteins described from IFN-induced human cells. The IRG2 message does not appear until 3 h after LPS exposure and its induction is dependent on new protein synthesis. IRG2 induction by LPS is slightly inhibited by the anti-inflammatory steroid, dexamethasone. Increasing cytosolic cAMP with either forskolin, dibutyryl cAMP, or 8-(4-chlorophenylthio)-cAMP caused marked inhibition of the LPS induction of IRG2. In contrast, activation of PKC with phorbol ester potentiated the LPS response. Removing extracellular Ca2+ with EGTA inhibited IRG2 induction; increasing intracellular calcium with the calcium ionophore A23187 led to enhanced levels of the IRG2 transcript. These data suggest that the induction of IRG2 occurs via a PKC pathway.
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PMID:Molecular cloning and characterization of a murine LPS-inducible cDNA. 820 6

It is well known that interferon-gamma (IFN-gamma; type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-gamma led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-gamma, IFN-alpha and IFN-beta (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C.
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PMID:Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2. Role of protein kinase C. 827 22

Protein kinases play key roles in the induction by human interferon alpha (IFN-alpha) of specific gene expression and biological activity in various human cell lines. We now report that IFN-alpha increased the 7-kb transcript for the epsilon isotype of protein kinase C (PKC-epsilon) and the cellular content of PKC-epsilon 24 and 48 hr after IFN-alpha addition (a 2-fold and 6-fold increase, respectively). Furthermore, IFN-alpha markedly induced a 4.7-kb transcript that hybridized to a PKC-epsilon-specific, but not to a PKC-eta-specific, cDNA probe. The induction of the 4.7-kb PKC-epsilon-related mRNA by IFN-alpha had the following properties reported for the classical IFN-alpha-stimulated genes: rapid kinetics of induction, high maintained levels in IFN-alpha-sensitive but not in IFN-alpha-resistant cell lines, protein synthesis-independent induction, and high sensitivity to inhibitors of protein tyrosine kinase activity. These results show that the regulation of gene expression by IFN-alpha include not only the classical IFN-alpha-stimulated genes but also the coordinated regulation of two PKC-epsilon-related transcripts that appeared to be highly relevant to the biological actions of IFN-alpha.
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PMID:Interferon alpha induces protein kinase C-epsilon (PKC-epsilon) gene expression and a 4.7-kb PKC-epsilon-related transcript. 834

We have recently shown that IFN alpha induces a cytolytic mechanism in human ovarian carcinoma cell lines which is revealed when protein synthesis is subsequently inhibited. In order to determine whether the cytolytic activity induced by IFN alpha was activated through a pathway involving the activation of PKC, the human ovarian carcinoma cell line Caov-3 was exposed to phorbol 12-myristate 13-acetate (PMA). Under conditions where PMA activates PKC, PMA mimicked IFN alpha in its ability to induce a cytolytic mechanism. In contrast, under conditions where PMA depletes PKC, PMA not only did not induce cytolytic activity, but it prevented IFN alpha from inducing cytolytic activity. To further investigate the involvement of PKC in the signaling of cytolytic activity by IFN alpha, the ability of the protein kinase inhibitors, staurosporine, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride (H7), N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8), and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide dihydrochloride (HA1004) to block the induction of cytolytic activity by IFN alpha was determined. The fact that H7, H8, and staurosporine, but not HA1004, blocked the induction of cytolytic activity by IFN alpha provides additional evidence of the involvement of PKC in this activity. Taken together these results indicate that the cytolytic activity induced by IFN alpha is induced through apathway that involves the activation of PKC.
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PMID:Interferon-alpha (IFN alpha) induces a cytolytic mechanism in ovarian carcinoma cells through a protein kinase C-dependent pathway. 837 36


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