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)

Possible involvement of protein phosphorylation in interferon (IFN)-mediated activation of IFN-stimulated gene factor 3 (ISGF3) was investigated. For this purpose, in vivo experiments with specific inhibitors of protein kinases and in vitro experiments with protein phosphatases were carried out. In HeLaM cells, 2-aminopurine, an inhibitor of double-stranded RNA-dependent protein kinase, blocked the induction of ISGF3 gamma subunit but not the activation of ISGF3 alpha subunit. A series of experiments using combinations of protein and RNA synthesis inhibitors and 2-aminopurine indicated that the block elicited by 2-aminopurine was at the level of ISGF3 gamma mRNA synthesis. Activation of ISGF3 alpha, although insensitive to 2-aminopurine, was completely blocked by 10 nM staurosporine, an inhibitor of protein kinase C. On the other hand, even 500 nM staurosporine did not block the induction of ISGF3 gamma. Incubation of cytoplasmic or nuclear extracts of IFN-treated HeLaM cells in vitro with alkaline phosphatase completely eliminated their ability to form the ISGF3 complex but not the ISGF1 complex. Treatment with acid phosphatase, on the other hand, changed the electrophoretic mobility of the ISGF3 complex but did not obliterate it. Complementation experiments revealed that ISGF3 alpha was the alkaline phosphatase-sensitive component of the complex. These results suggest that a protein kinase C-mediated phosphorylation step is involved in ISGF3 alpha activation and a 2-aminopurine-sensitive component is involved in ISGF3 gamma mRNA induction.
 ...
PMID:Role of protein phosphorylation in activation of interferon-stimulated gene factors. 155 41

Bryostatin 1, a potent activator of protein kinase C, has antitumor activity against murine lymphoma, leukemia, and melanoma. In vitro, this compound stimulates the release of gamma-interferon, interleukins, and hematopoietic growth factors from accessory cells and activates both T- and B-cells. Bryostatin 1 is also able to stimulate neutrophils to undergo oxidative burst and degranulation. Because of the ability of this compound to stimulate the immune system, cause release of immune mediators, and activate neutrophils, we have examined its effect on bacterial infection by using the gram-negative bacterium Salmonella typhimurium in mice. We find that animals given injections i.v. of S. typhimurium have a shortened life span if they are also given injections i.p. of nonlethal doses of bryostatin 1. There is a dose-response relationship with 100 micrograms/kg bryostatin 1 having a greater effect on survival than 40 micrograms/kg. Below 40 micrograms/kg there are no effects on survival. Analysis of the first 4 h of Salmonella infection demonstrates that bryostatin 1 does not affect the blood clearance of the bacterium. However, by day 2 of infection greater numbers of bacteria are found in the livers and spleens of mice given injections of bryostatin 1. By day 5, 10-fold more S. typhimurium bacteria are found in the livers and spleens of mice receiving 40 micrograms/kg of bryostatin 1. To determine whether bryostatin 1 was affecting growth or causing the death of bacteria, we used a Salmonella carrying a plasmid which has a temperature-sensitive origin of replication and is unable to replicate when the bacteria are in mice. This experiment demonstrates that bryostatin 1 represses bacterial killing but does not affect bacterial growth. Bryostatin 1 given i.p. stimulates a transient syndrome of weight loss and diarrhea from which the mice recover and regain weight, suggesting that bryostatin 1 may release a number of important humoral mediators in vivo. The weight loss is exacerbated by Salmonella infection with mice receiving bryostatin 1 and S. typhimurium, in that they lose approximately 33% of body weight prior to death. Thus, at doses used to treat murine tumors, bryostatin 1 treatment does not affect the clearance of S. typhimurium from the blood but does decrease the killing of bacteria in the liver and spleen, leading to early animal death. Such potential effects of bryostatin 1 on the outcome of bacterial infections should be evaluated in ongoing human trials of this agent.
 ...
PMID:In vivo administration of bryostatin 1, a protein kinase C activator, decreases murine resistance to Salmonella typhimurium. 155 18

To determine the cellular functions which are modified when interferon-beta (IFN-beta) gene expression is inhibited, a plasmid allowing the constitutive expression of RNA complementary to IFN-beta mRNA was constructed and stably introduced into L929 cells. Some of the selected clones expressing this antisense IFN-beta mRNA, named L-ASI, were unable to produce IFN-beta and lost the ability to arrest in the G0 phase of the cell cycle. Indeed, the usual transrepression of the c-fos gene observed in quiescent cells was blocked in IFN-beta antisense L-ASI clones and the c-fos gene was permanently stimulated. This overexpression of c-fos was not modified in response to protein kinase C agonists such as phorbol esters, but increased in response to the adenylate cyclase activator forskolin. In addition, the ability to induce major histocompatibility class I genes following recombinant IFN-beta treatment was impaired in antisense IFN-beta L-ASI clones, suggesting an important alteration of this cell with regard to the interferon system. Unexpectedly, the tumorigenicity of the clones was significantly diminished. We postulate that IFN-beta antisense RNA blocks the repression of the c-fos gene and thus prevents the arrest of cells in the G0 phase of the cycle.
 ...
PMID:An antisense interferon-beta RNA abolishes repression of c-fos gene expression. 159 42

We have stably overexpressed the human protein kinase C alpha (hPKC alpha) in NIH 3T3 fibroblasts under the control of the interferon (IFN) type I inducible murine Mx promoter. These cells showed a 10-fold increase in the transcription of hPKC alpha mRNA after induction with interferon alpha. The increase in the amount and activity of protein kinase C (PKC)-protein in these cells was only about 3-fold after induction with interferon alpha. Compared to control cells which were transfected with the vector only, the NIH 3T3 fibroblasts transfected with the hPKC alpha cDNA showed already a slightly increased PKC-activity and amount of PKC-protein in the absence of interferon alpha. The hPKC alpha overexpressing cells had an altered, "transformed-like" morphology, which was reversed by staurosporine, an increased growth rate and a higher saturation density. The growth rate was further increased by treating the cells with interferon alpha. The hPKC alpha overexpressing cells were able to grow in soft agarose after treatment with phorbol ester such as TPA (12-O-tetradecanoylphorbol 13-acetate). After phorbol ester and interferon treatment a stronger expression of the protooncogene c-jun was detectable in the hPKC alpha overexpressing cells, whereas expression of c-fos and c-myc was not affected. Since these cells show a specific response pattern due to induced PKC alpha expression they might be useful as an assay system for the development of PKC isozyme-specific inhibitors and activators.
 ...
PMID:Inducible overexpression of human protein kinase C alpha in NIH 3T3 fibroblasts results in growth abnormalities. 161 23

The hypothesis was tested that it is possible to influence cellular responses of intact cells using synthetic peptide substrates, pseudosubstrates, and inhibitors of protein kinases. Using cytotoxic T-cells (CTL), we demonstrate here that some basic amino acid-containing synthetic peptide substrates of protein kinases [e.g., of cGMP-dependent protein kinase (peptide PKG-S), synthetic peptide inhibitor of cGMP-dependent protein kinase (peptide PKG-I), and peptide corresponding to the tyrosine phosphorylation site in pp60src (peptide RR-src)] were strongly inhibitory in T-cell receptor (TCR) and T-cell growth factor, interleukin 2 (IL-2)-triggered proliferation of CTL. These peptides also inhibited other cellular responses of CTL. Peptides which contain basic amino acids, but do not have substrate specificity determinants for protein kinase, were not inhibitory. The inhibition with peptides is not due to their toxicity, since no cell death was observed by the trypan blue exclusion test and by lactate dehydrogenase release. Use of the granule exocytosis assay provided opportunities to clarify the mechanism of the peptide action. Tested peptides inhibited not only cell-surface ligand-induced CTL activation, but also affected cell-surface receptor-independent CTL activation (granule exocytosis and gamma-interferon secretion) induced by the synergistic action of the protein kinase C activator (PMA) and ionophore A23187. It was found that minor changes in amino acid composition or amino acid position in the synthetic peptides dramatically change their ability to affect lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Modulation of the effector functions of cytolytic T-lymphocytes with synthetic peptide inhibitors of protein kinases. 161 67

We have examined the mechanism of synergistic action occurring between interferon (IFN)-gamma and 12-0-tetradecanoylphorbol-13-acetate (TPA) with respect to the reduction of 125I-epidermal growth factor (125I-EGF) binding to human amnion (WISH) cells [Karasaki Y et al (1989) J Biol Chem 264: 6158-6163]. The cells were treated with protein kinase C (PKC) inhibitors (H7, staurosporine) to investigate the role of PKC in the synergism between IFN-gamma and TPA, since TPA is a strong activator of PKC. The combined effect of IFN-gamma and TPA was blocked by the PKC inhibitor, suggesting that PKC plays an important role in the synergistic action of TPA and IFN-gamma on the inhibition of EGF binding to the cells. The prolonged incubation (24 h) of the cells with TPA resulted in the restoration of EGF binding to the cells. A 24 h treatment of WISH cells with both IFN-gamma and TPA, however, still exhibited greater than 50% inhibition of EGF binding. No PKC activity, however, was observed in the WISH cells treated with both IFN-gamma and TPA for 24 h as well as with TPA alone for 24 h, indicating that IFN-gamma may synergize with the second mediator induced by PKC rather than PKC itself in the reduction of EGF binding to WISH cells. In addition, IFN-gamma showed the synergistic action with calcium ionophores on the reduction of EGF binding to the cells, suggesting that Ca2+ may be one of the second mediators which was induced by TPA and which cooperated with IFN-gamma.
 ...
PMID:The mechanism of the action of IFN-gamma and TPA on the modulation of epidermal growth factor receptors of human amnion cells. 162 Oct 11

(2'-5')Oligoadenylate [(2'-5')(A)n] synthetase is a key enzyme in the interferon-elicited antiviral response whose controlled expression in interferon-treated cells has been only partially elucidated. In this investigation, we have compared the modulation of the (2'-5')(A)n synthetase gene by interferon alone and by the combination of interferon and a second cellular effector, 12-O-tetradecanoyl-phorbol 13-acetate (TPA). Although TPA alone had no effect on (2'-5')(A)n synthetase, it potentiated the induction of (2'-5')(A)n of synthetase by interferon in HL-60 and HeLa cells by increasing content of its mRNA and an immunoreactive 40-kDa isoenzyme. Since TPA activates protein kinase C (PKC), other PKC-activating phorbol-ester analogues were tested and found to be effective, whereas the PKC inhibitor staurosporine reduced the potentiative activity of TPA. By using the (2'-5')(A)n synthetase gene promoter linked to a reporter gene, chloramphenicol acetyltransferase (CAT), TPA and interferon were found to result in a doubling of CAT activity compared to cells treated with interferon alone. Moreover, when nuclear extracts prepared from control cells or cells treated with TPA and interferon (IFN), separately or together, were incubated with radioactively labeled oligodeoxynucleotides containing the interferon-responsive element (IRE), TPA was shown to down-regulate an IFN-inducible IRE/protein complex. These data further suggest that TPA regulates (2'-5')(A)n synthetase gene expression at the level of transcription.
 ...
PMID:Transcriptional activation of human (2'-5')oligoadenylate synthetase gene expression by the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate in type-I-interferon-treated HL-60 and HeLa cells. 162 55

Several lines of evidence now exist to suggest an interaction between the platelet-derived growth factor (PDGF) growth-stimulatory signal transduction pathway and the beta interferon (IFN-beta) growth-inhibitory signal transduction pathway. The most direct examples are inhibition of PDGF-mediated gene induction and mitogenesis by IFN-beta and the effects of activators and inhibitors of the IFN-inducible double-stranded RNA-dependent eIF2 kinase on expression of PDGF-inducible genes. To further investigate the nature of this PDGF/IFN-beta interaction, we selected BALB/c-3T3 cells for resistance to growth inhibition by IFN-beta and analyzed the phenotypes of resulting clonal lines (called IRB cells) with respect to PDGF signal transduction. Although selected only for IFN resistance, the IRB cells were found to be defective for induction of growth-related genes c-fos, c-myc and JE in response to PDGF. This block to signal transduction was not due to loss or inactivation of PDGF receptors, as immunoprecipitation of PDGF receptors with antiphosphotyrosine antibodies showed them to be present at equal levels in the BALB/c-3T3 and IRB cells and to be autophosphorylated normally in response to PDGF. Furthermore, treatment with other peptide growth factors (PDGF-AA, fibroblast growth factor, and epidermal growth factor) also failed to induce c-fos, c-myc, or JE expression in IRB cells. All of these growth factors, however, were able to induce another early growth-related gene, Egr-1. The block to signaling was not due to a defect in inositol phosphate metabolism, as PDGF treatment induced normal calcium mobilization and phosphotidylinositol-3-kinase activation in these cells. Activation of protein kinase C by phorbol esters did induce c-fos, c-myc, and JE in IRB cells, indicating that signalling pathways distal to this enzyme remained intact. We have previously shown that IFN-inducible enzyme activities, including double-stranded RNA-dependent eIF2 kinase and 2',5'-oligoadenylate synthetase, are normal in IRB cells. The finding that the induction of multiple growth-related genes by several independent growth factors is inhibited in these IFN-resistant cells suggests that there is a second messenger common to both growth factor and IFN signaling pathways and that this messenger is defective in these cells.
 ...
PMID:BALB/c-3T3 fibroblasts resistant to growth inhibition by beta interferon exhibit aberrant platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor signal transduction. 164 46

In monocytes, sulfatide, a lipid from Mycobacterium tuberculosis, blocked priming for enhanced release of superoxide (O2-) by the macrophage activating factors lipopolysaccharide, gamma interferon, interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), and muramyl dipeptide. Sulfatide, in the presence of lipopolysaccharide, also caused increased secretion of IL-1 beta and TNF-alpha into monocyte culture medium. Sulfatide altered the pattern of phosphorylation of monocyte proteins. Cell lysates prepared from monocytes treated with sulfatide showed decreased activity of protein kinase C, but sulfatide did not directly inhibit protein kinase C activity when added to lysates. A known inhibitor of protein kinase C, staurosporine, also inhibited O2- release and caused increased secretion of IL-1 beta. Thus, sulfatide appeared to indirectly affect protein kinase C, implicating protein kinase C as part of the mechanism of priming. Because sulfatide blocked priming for enhanced release of O2-, which could interfere with monocyte bactericidal activity, while causing enhanced secretion of IL-1 beta and TNF-alpha, which could promote formation of granulomata, sulfatide might be an important factor in the pathogenesis of M. tuberculosis.
 ...
PMID:Monocyte responses to sulfatide from Mycobacterium tuberculosis: inhibition of priming for enhanced release of superoxide, associated with increased secretion of interleukin-1 and tumor necrosis factor alpha, and altered protein phosphorylation. 164 96

The biological activity of interferons (IFNs) is presumed to be mediated through the induction of a number of IFN-inducible genes. IFN-mediated gene induction was examined in two human breast cancer cell lines, MCF-7 and BT-20. Both these cell lines were remarkably responsive to IFNs as a number of IFN inducible genes were rapidly induced. We examined the sensitivity of these genes towards 2-aminopurine (2-AP), a known inhibitor of double-stranded (ds) RNA dependent protein kinase. 2-AP has also been reported to inhibit the induction of IFN-beta 1 in response to dsRNA and the genes c-myc and c-fos in fibroblasts. In both MCF-7 and BT-20 cell lines, 2-AP selectively inhibited the IFN-induced gene responses. 2-AP did not affect levels of the oncogene, HER-2/neu. Tamoxifen (TAM), an antiestrogenic drug, which is known to inhibit the activity of protein kinase C at high concentrations, did not affect IFN-mediated gene induction. Our data is consistent with the concept that the 2-AP sensitive kinase is primarily associated with the IFN-induced gene systems and that positive and negative growth regulating stimuli in breast cancer may require the participation of distinct kinases.
 ...
PMID:A distinct kinase modulates the expression of IFN-inducible genes in human breast cancer cells. 171 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>