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)

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

Cytosol (C) (100,000 x g/60 min, supernatant) from liver, brain and testis (Wistar male rats) are shown to contain insulin degrading activity (C-IDA). The regulation of C-IDA in these fractions by ligands that activate G protein and PKC were examined C-IDA from liver, brain and testis was inhibited 76%; 64% and 50% by 50 mM F- respectively. Chromatography of C fraction from liver on Sephadex G-50 in presence of 1 M (NH4)2SO4 and 20% (v/v) glycerol (experimental condition to remove guanine nucleotides from G proteins) decreased in about 3-fold aluminum fluoride effect on C-IDA. Mg++ (from 5mM to 10 mM) enhanced fluoride effects by inhibiting fully C-IDA. Phosphatidylserine in presence of ATP completely inhibited C-IDA; this inhibition was 31.3% mediated by a phosphorylation reaction. It is concluded that cytosol from different tissues contain proteins capable to associate ligands as aluminum fluoride and PS to regulate C-IDA. It is proposed a mechanism of protein-protein interaction to modulate C-IDA.
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PMID:Fluoride and phosphatidylserine induced inhibition of cytosolic insulin-degrading activity. 134 87

In rat cerebrocortical synaptosomes, the addition of 4 beta-phorbol dibutyrate (4 beta-PDBu) and arachidonic acid enhances and decreases, respectively, the glutamate release evoked by 4-aminopyridine. Pretreatment of synaptosomes with 12-O-tetradecanoylphorbol 13-acetate (TPA) or pre-incubation with staurosporine, prevent the stimulatory effect of 4 beta-PDBu, but are without effect on the inhibitory action of arachidonic acid. Moreover, methyl arachidonate, which is not effective as a PKC activator, also strongly inhibits glutamate exocytosis. These results suggest that PKC is not involved in the inhibition of glutamate release by arachidonic acid.
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PMID:PKC-independent inhibition of glutamate exocytosis by arachidonic acid in rat cerebrocortical synaptosomes. 134 20

We have studied the effects of staurosporine, an antagonist of the catalytic subunit of protein kinase C, on the mechanisms of long-term potentiation (LTP) in rat hippocampal slices maintained in vitro. Application of staurosporine did not affect pre-established LTP, but resulted in a decaying potentiation when high frequency stimulation was delivered in its presence. However, coactivation of two inputs to the same group of CA1 neurons during high frequency stimulation transformed the decaying potentiation into stable LTP. Staurosporine also reduced the NMDA receptor-mediated component of synaptic responses to burst stimulation. It is concluded that the PKC antagonist interferes with LTP induction, but not expression mechanisms.
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PMID:Induction of stable long-term potentiation in the presence of the protein kinase C antagonist staurosporine. 134 15

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 response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary arterial hypoxic contraction: signal transduction. 135 5

Cell surface aminopeptidases N (APN) and A (APA) have been characterized on cultured human glomerular epithelial cells and a SV40-transformed cell line derived from them. APN had a wide substrate specificity whereas APA only attacked peptides with an acidic N terminal amino acid. Both enzymes also differed by their sensitivity to divalent cations and to aminopeptidase inhibitors. Phorbolmyristate acetate (PMA) stimulated APN but not APA expression after a lag time of 12 hours. An increase of twice the basal value was observed with 10 ng.ml-1 PMA. This effect was confirmed by immunofluorescence staining using a specific anti-APN monoclonal antibody. Both ecto- and total enzyme activities were stimulated by PMA. The effect of PMA was suppressed by H7, a PKC inhibitor, and cycloheximide, an inhibitor of protein synthesis. Thrombin (1 to 2.5 U.ml-1) and interferon (IFN)-gamma (100 U.ml-1) also stimulated APN activity, the latter after longer exposure of the cells. APA activity was increased by 8-bromo-cAMP and two cAMP-stimulating agents, forskolin and isobutylmethylxanthine (IBMX). A twofold increase above basal value was obtained with 100 microM forskolin after 72 hours of treatment. cAMP-stimulated APA activity was suppressed by cycloheximide. Dexamethasone also stimulated APA activity. The effects of forskolin and dexamethasone were additive. These results demonstrate that APN and APA in glomerular epithelial cells are under different regulations: mitogens and IFN-gamma for APN, cAMP and glucocorticoids for APA. This selective expression may imply possible functional consequences in glomerular diseases.
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PMID:Cell surface aminopeptidase A and N activities in human glomerular epithelial cells. 135 70

We studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in primary cell cultures derived from fetal rats at embryonic day E14. The effects of compounds which activate these second messenger systems were compared to those of basic fibroblast growth factor (bFGF) and insulin-like growth factor I (IGF-I). In mesencephalic cultures, there was a continuous loss of dopaminergic neurons. Despite this decline in cell number, neurotransmitter uptake per neuron increased with time, indicating that the surviving dopaminergic neurons continued their biochemical differentiation while others degenerated. IGF-I and bFGF did not affect the number of dopaminergic neurons. However, dopamine uptake per neuron was significantly higher in bFGF and IGF-I treated cultures, suggesting that these factors stimulated differentiation. Protein kinase C and cAMP-dependent protein kinases were not involved in mediating the effects of bFGF and IGF-I. Treatment of cultures with phorbol esters did not affect dopamine uptake, whereas elevated levels of intracellular cAMP resulted in an increase in dopamine uptake which was additive to that elicited by bFGF or IGF-I. Further analysis revealed that exposure of mesencephalic cultures to dibutyryl cAMP (dbcAMP) during the first 3 days after plating increased the survival of dopaminergic neurons, whereas prolonged treatment attenuated the development of the dopamine uptake system. Moreover, cyclic AMP, but not bFGF, was able to prevent the degeneration of dopaminergic neurons induced by 1-methyl-4-phenyl-pyridinium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results suggest that increased intracellular levels of cAMP protect dopaminergic neurons in situations of stress like the process of dissociation and plating or the exposure to neurotoxic compounds. Our results reveal novel possibilities for the treatment of Parkinson's disease.
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PMID:Cyclic AMP, but not basic FGF, increases the in vitro survival of mesencephalic dopaminergic neurons and protects them from MPP(+)-induced degeneration. 135 86

Synaptoneurosomes, incubated with amphetamine, showed a biphasic dose-response change in activity of PKC and release of DA. Activity of particulate PKC activity and release of DA were decreased at 0.01-10.00 nM, while activity of both was increased at 1-10 microM. The effects of 0.1 nM amphetamine were attenuated by pretreatment with N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a peptide-coupling agent which inactivated DA receptors. They persisted if the autoreceptors were protected with sulpiride or apomorphine (0.05 mg/kg), prior to the treatment with EEDQ. In these protected rats, the amphetamine-induced change in activity of PKC was attenuated by sulpiride. In contrast, the effects of the larger doses of amphetamine on the activity of PKC were not affected by pretreatment with EEDQ. Subcellular fractionation of tissues, incubated with 1 microM amphetamine, showed an increase in activity of particulate PKC, only in the synaptic plasma membrane fraction, while tissues incubated with reserpine showed a decrease in activity of particulate PKC, only in the vesicular fraction. Similar results were seen when synaptic plasma membrane or synaptic vesicles were incubated directly with amphetamine or reserpine. These findings suggest the presence of multiple metabolic pools of PKC: a reserpine-sensitive pool, present in synaptic vesicles and an amphetamine-sensitive pool, present in the synaptic plasma membrane. That the latter pool of PKC may be involved in the transport of DA was indicated by the good correlation between the ability of drugs to inhibit the activity of PKC and their ability to inhibit the amphetamine-induced release of DA.
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PMID:Protein kinase C and dopamine transport--2. Effects of amphetamine in vitro. 136 66

Cross-resistance to anticancer drugs, termed multidrug resistance (MDR), is functionally associated with the expression of a plasma membrane, energy-dependent, drug efflux pump termed P-glycoprotein (PGP), the product of the mdr1 gene. We have shown previously that MCF-7 breast carcinoma cells transfected with the human mdr1 gene (BC-19 cells) exhibit greater MDR when stably transfected with protein kinase C alpha (PKC alpha). We now demonstrate that transfection of BC-19 cells with the gamma isoform of PKC (BC-19/PKC gamma cells), which is not normally present in BC-19 cells, does not confer increased resistance to doxorubicin, despite a 19-fold increase in PKC activity. All of the increased PKC activity is accounted for by PKC gamma and it is rapidly down-regulated by phorbol dibutyrate, within 15 min of treatment. Endogenous PKC alpha and PKC epsilon activities are not affected by phorbol dibutyrate. The cytotoxicity of doxorubicin was similar in BC-19/neo or BC-19/PKC gamma cells after either 2-hr or continuous drug exposure, and co-treatment with phorbol dibutyrate increased resistance to doxorubicin 4-fold in both cell lines. Phosphorylation of PGP was similar in both cell lines and drug accumulation was not affected by overexpression of PKC gamma. These results demonstrate that transfection of PGP-expressing cells with an atypical isoform of PKC does not confer increased MDR, and they suggest that the regulation of PGP is phenotype specific with respect to the isoform of PKC.
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PMID:Role of protein kinase C in the modulation of multidrug resistance: expression of the atypical gamma isoform of protein kinase C does not confer increased resistance to doxorubicin. 136 42


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