Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that expression of the c-jun proto-oncogene is induced by phorbol esters and other agents that activate protein kinase C. The present work has examined the involvement of cAMP-dependent signaling mechanisms in the regulation of c-jun gene expression. Low levels of c-jun transcripts were detectable in untreated HL-60 myeloid leukemia cells. In contrast, treatment of these cells with 8-bromoadenosine 3',5'-cyclic monophosphate was associated with increases in c-jun expression that were maximal at 3 h and then declined to pretreatment levels. Similar findings were obtained with N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate and 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, but not with 8-bromoguanosine 3',5'-cyclic monophosphate. c-jun transcripts were also increased with agents, such as prostaglandin E2 and forskolin, that increase intracellular cAMP levels. The effects of these agents on c-jun expression were associated with activation of cAMP-dependent protein kinase. Moreover, inhibition of this kinase activity with the isoquinolinesulfonamide derivative H8 was associated with a block in the induction of c-jun expression by cAMP. Nuclear run-on analysis further demonstrated that while c-jun transcription is a low levels in untreated HL-60 cells, treatment with cAMP analogs is associated with an increase in the transcriptional rate of this gene. Taken together, these findings suggested that, in addition to activation of protein kinase C, stimulation of cAMP-dependent protein kinase activity is also involved in the transcriptional induction of c-jun gene expression. The present results similarly demonstrate that c-fos gene transcription is induced in HL-60 cells through a mechanism involving cAMP-dependent protein kinase activity. Since heterodimers of the Jun and Fos proteins have been shown to bind to the phorbol ester-responsive element (AP-1-binding site), the present findings indicate that cAMP-induced signaling events may also regulate gene transcription through formation of Fos/Jun heterodimers and that interaction between phorbol ester- and cAMP-dependent pathways could occur through induction of the c-jun gene in these cells.
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PMID:Regulation of c-jun gene expression by cAMP in HL-60 myeloid leukemia cells. 217 93

Several growth factors and mitogens have been shown to activate the proto-oncogene product Raf-1 protein kinase in murine fibroblasts, apparently through a direct agonist-stimulated tyrosine phosphorylation of the Raf-1 protein. We investigated the possibility that insulin could also activate the Raf-1 kinase, since its receptor also contains an intrinsic insulin-activated protein tyrosine kinase activity. In several cell lines expressing relatively large numbers of insulin receptors, insulin rapidly stimulated the phosphorylation of immunoreactive Raf-1 protein. In H35 cells, a line of well differentiated rat hepatoma cells, the effect of insulin was maximal by 6 min and at 7 nM insulin and occurred normally in cells virtually completely depleted of protein kinase C activity. The insulin-stimulated increase in Raf-1 protein phosphorylation occurred concurrently with a 3-fold increase in Raf-1 protein kinase activity. However, phosphoamino acid analysis showed that only phosphoserine and a trace of phosphothreonine were present in the Raf-1 protein after insulin stimulation of the cells. This was true even when investigated at shorter times (4 min) after insulin stimulation and despite the use of phosphotyrosine phosphatase inhibitors. We conclude that insulin can rapidly activate the Raf-1 kinase in some insulin-sensitive cell types but that this activation probably occurs through a mechanism distinct from direct phosphorylation of the Raf-1 protein by the insulin receptor protein tyrosine kinase.
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PMID:Insulin activates the Raf-1 protein kinase. 219 71

Microglia were isolated from primary mixed brain cell culture of normal newborn mice and then cultivated. They were able to be maintained in vitro for 1-2 months, but incorporated little [3H]thymidine under normal culture conditions. When treated with the conditioned medium of L929 mouse fibroblast cells as a crude CSF-1 (mouse macrophage-colony stimulating factor) or purified CSF-1, microglia showed morphological changes and increased in both cell number and [3H]thymidine uptake. In addition, crude CSF-1 increased lysosomal enzyme activity and superoxide anion formation of microglia up to 2 and 3.8 fold as control value, respectively. These effects of CSF-1 were not observed in the purified astrocyte culture. Purified microglia had CSF-1 receptors which were recognized by the anti-CSF-1 receptor antibody that arose from a peptide of a product of proto-oncogene, c-fms. 12-O-Tetradecanoylphorbol-13-acetate (TPA) also increased microglia cell number and their biochemical activities, suggesting the possible involvement of protein kinase C activation. Protein kinase inhibitors, such as staurosporine or H-7, inhibited the effects of both CSF-1 and TPA. These results indicate that microglia may be regulated in its biochemical and proliferation activities by CSF-1 and that this may occur via activation of protein kinase C.
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PMID:Activation and proliferation of the isolated microglia by colony stimulating factor-1 and possible involvement of protein kinase C. 230 29

Transcription of the c-fos proto-oncogene is rapidly induced by serum growth factors. A short c-fos DNA element, the serum response element (SRE), is required for this response to serum. However, serum activates a series of distinct intracellular signaling pathways, and it is not known to which of these pathways the SRE responds. To address this question, mutations have been introduced into the SRE of an otherwise intact c-fos promoter/enhancer. These mutations strongly reduce the binding of a nuclear factor to this site. Plasmids carrying either a wild-type or mutant c-fos SRE were transfected into fibroblasts and tested for their response to whole serum, purified recombinant c-sis protein, the protein kinase C activator phorbol myristate acetate, and activators of the cyclic AMP (cAMP) second messenger system. Assays were carried out under normal conditions and after chronic phorbol ester-treatment to deplete phorbol ester activatable protein kinase C activity from transfected cells. The results show that the SRE is necessary and sufficient for response to both protein kinase C-dependent and -independent intracellular signaling pathways but not for response to the cAMP pathway.
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PMID:The c-fos serum response element responds to protein kinase C-dependent and -independent signals but not to cyclic AMP. 245 93

The first monoclonal antibodies (MoAbs) to epitopes in the extracellular domain of the human c-fms proto-oncogene product (receptor for the macrophage colony stimulating factor, CSF-1) were used with flow cytometric techniques to study receptor expression on normal human peripheral blood monocytes, bone marrow cells, and leukemic blasts. On normal cells CSF-1 receptors were restricted in their expression to cells of the mononuclear phagocyte lineage. CSF-1 receptors were detected on leukemic blasts from 15 (30%) of 50 children with acute myeloid leukemia, compared with four (15%) of 26 adults. By contrast, detectable CSF-1 receptors were uniformly absent on blasts from 19 children with acute lymphoblastic leukemia. CSF-1 receptors on normal monocytes and myeloid leukemia cells could be induced to downmodulate by incubation with either human recombinant CSF-1 or phorbol esters, confirming that the receptors had functional ligand-binding sites and responded to transmodulation by inducers of protein kinase C. The numbers of receptors per cell and the percentage of positive cases were highest for leukemic blasts with cytochemical and morphological features of monocytes. However, CSF-1 receptors were also detected on a subset of leukemic blast cells with features of granulocytic differentiation (FAB subtypes M1 through M3). Southern blotting analyses of DNA from 47 cases of acute myeloid leukemia demonstrated no rearrangements within the 32 kb of genomic sequences that contain CSF-1 receptor coding exons or in the 50 kb upstream of the first coding exon. Analysis of the upstream region of the c-fms locus revealed that sequences representing the terminal 112 untranslated nucleotides of c-fms mRNA map 26 kb 5' to the first coding exon, suggesting that at least one c-fms promoter is separated from the receptor coding sequences by a very long intron. Whereas expression of the CSF-1 receptor in myeloid leukemic blasts is not restricted to cells with monocytic characteristics, the apparently aberrant pattern of receptor synthesis in a subset of cases with granulocytic features appears not to be due to chromosomal rearrangements within 50 kb upstream of sequences encoding the receptor.
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PMID:Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on normal mononuclear phagocytes and on human myeloid leukemic blast cells. 246 43

Insulin and phorbol esters have been shown to produce similar, non-additive metabolic effects in BC3H-1 murine myocytes. Recently, it has been demonstrated that insulin stimulation of these cells increases production of diacylglycerol, a known activator of protein kinase C (PK-C). To determine if insulin stimulation results in the activation of PK-C, we have examined the effects of insulin and the tumor promoting phorbol ester, 12-0-tetradecanoyl-phorbol-13-acetate (TPA), on the phosphorylation of a known PK-C substrate in vivo, the cellular proto-oncogene product, pp60c-src. Differentiated BC3H-1 monocytes showed an approximate twofold elevation in the [32P] content of pp60c-src following stimulation with insulin or TPA for 20 min, with no detectable change in the level of immunoprecipitable c-src protein. The enhanced phosphorylation in response to each agent localized to serine residues in the amino terminal 16 kD staphylococcal V8 proteolytic fragment. Tryptic phosphopeptide analysis revealed that TPA stimulation resulted in an approximate 18-fold increase in phosphorylation of the serine 12-containing tryptic fragment. Insulin stimulation, however, resulted in an approximate 10-fold increase in phosphorylation of the serine 17-containing tryptic fragment with little or no accompanying increase in serine 12 phosphorylation. In cells exposed to high concentrations of TPA for 16 h to deplete PK-C activity, insulin, but not TPA, stimulated phosphorylation of pp60c-src. These data suggest that insulin and phorbol ester induce phosphorylation of pp60c-src by distinct protein kinases.
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PMID:Insulin and phorbol ester induce distinct phosphorylations of pp60c-src in the BC3H-1 murine myocyte cell line. 246 25

The product of the c-src proto-oncogene, pp60c-src, is phosphorylated at Ser-17 by cyclic AMP-dependent protein kinase A and at Ser-12 by calcium-phospholipid-dependent protein kinase C (when stimulated by 12-O-tetradecanoyl phorbol acetate). We tested the effects of Ser----Ala and Ser----Glu mutations at these sites in pp60c-src and in pp60c-src(F527) (a mutant whose transforming activities are enhanced by Tyr-527----Phe mutation) by transfecting single-, double-, and triple-mutant src expression plasmids into NIH 3T3 cells. Tryptic phosphopeptide analyses of the mutant proteins confirmed prior biochemical identifications of the phosphorylation sites and showed that neither separate nor coordinate mutations at Ser-12 and Ser-17 affected Tyr-416, Tyr-527, or Ser-48 phosphorylation or prevented mitosis-specific phosphorylations of either pp60c-src or pp60c-src(F527). Ser-12 mutation did not affect phosphorylation of the Ser-17-containing peptide, but mutation of Ser-17 significantly increased phosphorylation at Ser-12. Specific kinase activities (both with and without in vivo 12-O-tetradecanoyl phorbol acetate treatment) and the abilities of pp60c-src and pp60c-src(F527) to induce foci, transformed morphologies, and anchorage-independent growth were unaffected by any of the serine mutations. Thus, pp60c-src transforming activity in NIH 3T3 cells is relatively insensitive to phosphorylation at these sites, but there is a suggestion that Ser-17 phosphorylation may have a subtle regulatory effect.
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PMID:Mutation of amino acids in pp60c-src that are phosphorylated by protein kinases C and A. 247 54

The effects of the cytokine IL-4 on resting and activated human B cells were compared with the effects of known "competence" signals able to drive resting B cells into the cell cycle, including anti-Ig, PMA, anti-CD20, and a recently described competence signal, anti-Bgp95. In proliferation assays, IL-4 was costimulatory with anti-Ig and anti-Bgp95 but not with anti-CD20 or PMA. IL-4 alone triggered increases in expression of class II DR/DQ and CD40, but it did not trigger increases in intracellular free calcium [Ca2+]i in resting B cells or induce resting B cells to leave G0 and enter the G1 phase of the cell cycle. Although IL-4 has some characteristics of competence signals, it was most effective if added to B cells up to 12 h after anti-Ig or anti-Bgp95 rather than before, and thus, in this respect, works more like a progression signal. Like IL-4, all four competence signals for B cells triggered increases in class II and CD40, but only IL-4 consistently induced increases in CD23 surface levels. IL-4 was costimulatory only with anti-Ig and anti-Bgp95, each of which can trigger increases in [Ca2+]i and new protein synthesis of the proto-oncogene c-myc, and can increase attachment of protein kinase C to the plasma membrane. IL-4 was not costimulatory with signals that 1) did not affect [Ca2+]i yet induced c-myc protein synthesis (anti-CD20), 2) only stimulated the translocation of protein kinase C (PMA), or 3) only stimulated increases in [Ca2+]i (calcium ionophore). These results suggest that resting human B cells require at least two intracytoplasmic signals before IL-4 can effectively promote B cell proliferation.
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PMID:Activation of human B cells. Comparison of the signal transduced by IL-4 to four different competence signals. 248 Mar 76

Rat pheochromocytoma PC12 cells differentiate to sympathetic neuron-like cells upon treatment with nerve growth factor (NGF). The ras and src transforming proteins also induce PC12 neuronal differentiation and are likely to involve the protein kinase C signal transduction pathway. Using a number of ras mutants, we have established that the domains of oncogenic ras protein responsible for PC12 differentiation overlap those required for cellular transformation. All of the ras mutants that induced neuronal differentiation also activated c-fos transcription through the dyad symmetry element (DSE). Transforming ras protein activated an intracellular signal pathway, which led to the induction of 12-O-tetradecanoyl phorbol-13-acetate-responsive elements; activation was enhanced by coexpression of the proto-oncogene jun (encoding AP-1) and was further augmented by fos. Nuclear extracts from ras-infected PC12 cells showed an increased AP-1 DNA-binding activity. Transcriptional activation by ras was independent of the cyclic AMP-dependent pathway of signal transduction. We propose a possible involvement of fos and jun in ras-induced differentiation.
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PMID:ras-induced neuronal differentiation of PC12 cells: possible involvement of fos and jun. 250 2

The turnover of the colony-stimulating factor 1 receptor (CSF-1R), the c-fms proto-oncogene product, is accelerated by ligand binding or by activators of protein kinase C (PKC), such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The mechanisms of ligand- and TPA-induced downmodulation were shown to differ by the following criteria. First, in cells in which PKC was downmodulated, CSF-1R reexpressed at the cell surface remained sensitive to ligand but was refractory to TPA-induced degradation. Second, a kinase-defective receptor containing a methionine-for-lysine substitution at amino acid 616 at its ATP-binding site failed to undergo ligand-induced downmodulation but remained responsive to TPA. Following CSF-1 stimulation, no intermediates of receptor degradation could be immunoprecipitated with polyvalent antisera to CSF-1R. In contrast, TPA induced specific proteolytic cleavage of the receptor near its transmembrane segment, resulting in the release of the extracellular ligand-binding domain from the cell and the generation of an intracellular fragment containing the kinase domain. Two-dimensional phosphopeptide mapping demonstrated no new sites of phosphorylation in response to TPA in either the residual intact receptor or the intracellular proteolytic fragment. Therefore, PKC appears not to trigger downmodulation by directly phosphorylating the receptor but, rather, activates a protease which recognizes CSF-1R as a substrate.
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PMID:Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms. 252 80


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