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 have earlier found that in Jurkat cells activation of protein kinase C (PKC) enhances the cyclic adenosine monophosphate (cAMP) accumulation induced by adenosine receptor stimulation or activation of Gs. Here we have therefore examined the effect of the phorbol ester PMA (phorbol 12-myristate 13-acetate) which stimulates PKC and a combination of the adenosine receptor agonist NECA (5'-(N-ethyl)-carboxamido adenosine) and forskolin to raise cAMP, on the levels of c-Fos and Jun and on the binding and transcriptional activity of the transcription factor, activator protein-1 (AP-1). PMA treatment caused a concentration- and time-dependent increase in both c-Fos and Jun immunoreactivity in contrast to cAMP elevation that had only a slight effect. Both PMA and the combination of NECA and forskolin acted together either to increase (c-Fos) or decrease (Jun) protein levels as well as increasing AP-1 binding, as judged by gel-shift assay, and AP-1 transcriptional activity. Furthermore there was a clear-cut synergy between the PKC stimulator and the cAMP elevating agents. The results demonstrate that the simultaneous activation of PKC and elevation of cAMP leads to an enhanced AP-1 transcriptional activity in a T-leukemia cell line, suggesting that the previously observed interaction between the parallel signal transduction pathways may have functional consequences at the level of gene transcription.
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PMID:Activation of protein kinase C and elevation of cAMP interact synergistically to raise c-Fos and AP-1 activity in Jurkat cells. 133 18

In cultured cortical collecting duct (CCD) cells, exogenous prostaglandin E2 (PGE2) inhibited arginine vasopressin (AVP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production in a concentration-dependent manner. Although pertussis toxin (PT, 500 ng/ml) alone did not reverse the PGE2-dependent inhibition, PT and staurosporine, a protein kinase C inhibitor, together partially reversed the effect of exogenous PGE2. In contrast, PT completely reversed the inhibition of AVP-dependent cAMP production by sulprostone. These data suggest that exogenous PGE2 can inhibit AVP-stimulated cAMP production and that the inhibitory effects of PGE2 are mediated by staurosporine- and PT-sensitive component(s). Short-term (15-240 min) incubation with phorbol 12-myristate 13-acetate (PMA, 10(-7) M) inhibited PGE2-stimulated cAMP production. Long-term (20 h) incubation with PMA augmented PGE2-stimulated cAMP production. These data provide evidence for the maintenance of a PT-sensitive PGE2-dependent inhibitory pathway of cAMP production in cultured CCD cells. In addition, data are presented that support an inhibitory role for protein kinase C in the effects of PGE2 on the metabolism of cAMP in these cells.
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PMID:PGE2 regulates cAMP production in cultured rabbit CCD cells: evidence for dual inhibitory mechanisms. 133 88

In UMR-106 osteosarcoma cells we found that PTH activated both the cAMP/protein kinase A and the Ca(2+)-dependent phosphoinositide/protein kinase C (PKC) pathways, but prostaglandin E2 (PGE2) activated only the cAMP pathway. Activation of PKC by the phorbol ester PMA had no effect on cAMP production but enhanced PTH-stimulated cAMP production by 50% or more; the effect on PGE2-induced cAMP was negligible. Inhibition of the alpha-subunit of the inhibitory guanine nucleotide binding protein (Gi) by pertussis toxin pretreatment also enhanced PTH-mediated cAMP production but had no effect on PGE2-induced cAMP production. These results suggest that although PTH-mediated adenylate cyclase activity is regulated via both the stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, only Gs regulates PGE2-mediated adenylate cyclase activity in UMR-106 cells. Costimulation with pertussis toxin and PMA did not increase PTH-stimulated cAMP production above that obtained with PMA alone. This implies a similar target of action for pertussis toxin and PMA, that is, the alpha-subunit of Gi. The alpha-subunit of Gi was found to be a substrate for in vitro PKC phosphorylation of membrane fractions from UMR-106 cells, seen as a +/- 40 kD band on SDS-PAGE. Stimulation of in situ 32P-labeled cells with either PMA or PTH also enhanced incorporation of 32P into the 40 kD band. Using the peptide antisera AS/7 and EC/2, we showed that pertussis toxin-labeled subunits of both Gi1 alpha/Gi2 alpha and Gi3 alpha could be immunoprecipitated, respectively, but immunoprecipitation of membrane proteins after in situ phosphorylation and stimulation with PMA precipitated only Gi2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C modulates parathyroid hormone- but not prostaglandin E2-mediated stimulation of cyclic AMP production via the inhibitory guanine nucleotide binding protein in UMR-106 osteosarcoma cells. 133

The mucus producing colonic cell line, LS174T, was used as a model to study E. histolytica-induced mucin secretion. E. histolytica trophozoites in contact with the mucus layer overlying the LS174T cells and in response to PMA, a protein kinase C activator, and Ca2+ ionophore A23187 which elevates intracellular Ca2+ ([Ca]i), caused a time-dependent (0.25-2.00 h) release of mucin. PKC inhibitors, H7 and staurosporine inhibited E. histolytica (37 and 75%) and PMA (46 and 100%)-induced mucin secretion, whereas in response to Ca2+ ionophore mucin secretion was augmented (56 and 17%). Both PMA and E. histolytica-induced the translocation of the PKC enzyme from the cytoplasm to the membrane fraction with increased enzyme activity. These results suggest that even though mucin secretion can be induced by PKC and Ca(2+)-dependent pathways, E. histolytica evokes the fast release of mucins by a PKC-dependent mechanism.
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PMID:The fast release of mucin secretion from human colonic cells induced by Entamoeba histolytica is dependent on contact and protein kinase C activation. 134 Feb 98

Ligation of the TCR on Jurkat T lymphoblastoid cells causes an 1,4,5-inositol trisphosphate-dependent rise in intracellular cytoplasmic calcium that is inhibited by PMA, a potent activator of protein kinase C. Consequently, protein kinase C is widely believed to mediate feedback inhibition of TCR-activated phospholipase C. We have now extended these studies to normal unblasted human CD4+ T lymphocytes, examining the PMA sensitivity of both the TCR complex-mediated release of total inositol-phosphates and the resynthesis of the parent phosphoinositides. In contrast to Jurkat, in which PMA inhibited release of 1,4,5-inositol trisphosphate by 60% and total inositolphosphates by 40% (50% inhibitory concentration, 5.6 nM), normal cells displayed a marked increase in anti-CD3-induced phosphatidylinositol (PI) cycling in the presence of PMA. Both total inositolphosphate release and PI resynthesis were maximally elevated (88% and 342%, respectively) by a PMA concentration that also optimally supported a subsequent proliferative response; the ED50 was at least 11.7-fold lower than that for the inhibitory effect of PMA on breakdown of total Jurkat PI. A PKC nonactivating phorbol ester had no effect. If anti-CD3 was replaced by the mitogenic lectin PHA, PI resynthesis was similarly up-regulated by PMA in these highly purified cells. The PMA up-regulatory phenomenon was not a simple consequence of cell blastogenesis, inasmuch as there was no early effect on the non-signaling-associated phosphatidylethanolamine compartment after CD3 stimulation. Thus, PKC activation appears to accelerate TCR-linked PI metabolism in normal Th cells, in contrast to the feedback inhibitor paradigm observed in Jurkat and other tumor cell systems.
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PMID:A protein kinase C-activating phorbol ester accelerates the T cell antigen receptor-stimulated phosphatidylinositol cycle in normal human CD4+ T cells. 134 21

The defective virus found in the LP-BM5 mixture of murine leukemia viruses induces a severe immune deficiency disease in C57BL/6 mice that is characterized by the activation and expansion of T and B cells that become unresponsive to normal immune stimuli. The nature of the biochemical lesion in these defective lymphocyte populations remains unknown. Flow cytometric analysis of the T cell population in infected animals has demonstrated expansion of both CD4+ and CD8+ subsets. Despite chronic expansion in vivo, CD4+ T cells by wk 4 postinfection failed to up-regulate cell surface IL-2R expression, produced IL-2, or proliferate in vitro in response to either Con A, Staphylococcal enterotoxin super-antigens, or anti-CD3 stimulation. Exogenous IL-2 did not restore the proliferative response and also failed to up-regulate IL-R expression on CD4+ T cells from infected mice, even though basal IL-2R expression was initially elevated compared to normals. In contrast, CD4+ T cells from infected mice could be induced to proliferate by stimulation with PMA and ionomycin resulting in IL-2R up-regulation, IL-2 production, and proliferation. Moreover, proliferation could also be induced by anti-CD3 plus PMA, although anti-CD3 plus ionomycin was without effect. These studies suggest that chronic expansion of CD4+ T cells in infected mice is probably not maintained by normal TCR signaling, which appears defective in these cells. In addition, the lesion in biochemical signaling appears to result in defective activation of protein kinase C, which can be overcome by direct activation with PMA.
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PMID:T-deficient transmembrane signaling in CD4+ T cells of retroviral-induced immune-deficient mice. 135 Feb 88

We have described the isolation of chemically induced CEM subclones that express CD4 receptors and bind soluble gp120, yet show a markedly reduced susceptibility to infection with HIV-1. Two subclones were found to have an abnormal response to the protein kinase C (PKC) activator PMA. PMA treatment induced CD3 and CD25 (IL-2R) receptors on the parental line and on other ethyl-methanesulfonate-derived subclones, but not on these two mutants. Direct assays of PKC activity were conducted. Total cellular PKC enzymatic activity was found to be normal in these subclones. PMA-induced CD4 down-modulation occurred normally. In addition, activation of c-raf kinase was normal. Since HIV-1 long terminal repeat contains two functional nuclear factor kB (NF-kB) regulatory elements, we studied the ability of PMA to induce NF-kB binding activity by different assays. Chloramphenicol acetyl transferase (CAT) assays using the HIV-1 (-139)long terminal repeat-CAT construct showed no PMA induction of CAT activity in these subclones (unlike the parental line and other subclones). Okadaic acid, an inhibitor of phosphatases 1 and 2A, did not overcome the defect in these subclones. Gel retardation assays, using a 32P-probe containing the HIV-1 NF-kB probe and nuclear extracts from PMA-treated cells, showed significantly reduced induction of nuclear NF-kB binding proteins in these two subclones compared with wild type CEM and a control subclone. Deoxycholate treatment of cytoplasmic extracts from these subclones released much reduced NF-kB binding proteins from their cytoplasmic pools. Thus, reduced levels of PKC-induced nuclear NF-kB activity in two T cell subclones did not affect their normal cell growth, but correlated with a pronounced reduction in their susceptibility to HIV-1 infection.
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PMID:Reduced susceptibility to HIV-1 infection of ethyl-methanesulfonate-treated CEM subclones correlates with a blockade in their protein kinase C signaling pathway. 135 Oct 90

Ag independent adhesion between lymphocytes and target cells is mediated in part by the interaction between lymphocyte function associated Ag-1 (LFA-1) and its coreceptor intercellular adhesion molecule-1 (ICAM-1). Within minutes, PMA treatment of JY cells, which express both LFA-1 and ICAM-1, induced capping of LFA-1 and augmentation of intercellular adhesion lasting for several hours. However, over the course of 15 to 30 min, both of these events were blocked by elevation of intracellular cAMP concentration ([cAMP]i) presumably via activation of protein kinase A. This short term inhibition of protein kinase C-induced adhesion was in contrast to the long term augmentation of adhesion caused by increased [cAMP]i as demonstrated in the companion article. Intercellular adhesion, due to LFA-1/ICAM-1 interactions, could also be induced by LPS treatment of JY cells. At submaximal concentrations, the extent of aggregation induced by LPS had two maxima, one at 30 to 60 min and the other with a plateau at 5 to 8 h. LPS is known to activate protein kinase C and we show that LPS treatment induced increased [cAMP]i. Using inhibitors of protein kinases C and A, possible mediators of the two components of adhesion induced by LPS could be identified. The early component was abrogated by inhibition of protein kinase C although the later component was unaffected. In contrast, an inhibitor of protein kinase A had no affect on the early component and attenuated, but did not entirely eliminate, the late component. These results suggest a model of sequential induction, inhibition, and reinduction of LFA-1/ICAM-1-mediated lymphocyte adhesion that is regulated by temporally ordered actions and interactions of protein kinases C and A.
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PMID:Lymphocyte adhesion mediated by lymphocyte function-associated antigen-1. II. Interaction between phorbol ester- and cAMP-sensitive pathways. 135 28

We have investigated the direct effect of copper on malondialdehyde formation in rat isolated hepatocytes. Copper was found to decrease the cell viability with concomitant production of malondialdehyde in a time related manner. In addition the protein kinase C activator, PMA, was found to have a synergistic effect with copper on rat hepatocytes. These results indicate that protein kinase C may be important in mediating hepatotoxicity after exposure to copper.
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PMID:Effect of exogenous copper on lipid peroxidation in rat hepatocytes. Possible involvement of protein kinase C. 135 45

1. Voltage-clamp recordings have been made from identified neurones in the suboesophageal ganglia of Helix aspersa. 2. Calcium currents were isolated pharmacologically and studied under two-electrode voltage-clamp. 3. PdBu but not PMA caused a transient enhancement followed by an irreversible inhibition of the calcium current. 4. It is concluded that activation of protein kinase C within these neurones may show selectivity with respect to the exogenous activator used.
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PMID:The actions of phorbol esters upon isolated calcium currents of Helix aspersa neurones. 135 45


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