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 measured the activities of UDP-galactose:globotriaosylceramide alpha 1-3-galactosyltransferase (alpha-GalTase) and protein kinase C (PKC) in PC12D pheochromocytoma (PC12D) cells which were induced to differentiation by nerve growth factor (NGF), forskolin (FRK), staurosporine (STP), retinoic acid (RA), 2-chloroadenosine (ClAd), and/or galactosylceramide (GalCer). NGF, STP, FRK, and RA were found to be stimulators for the PKC activity, whereas ClAd appeared to be an inhibitor of the enzyme. At the concentration of 25 microM, GalCer having normal fatty acids was found to be a stimulator, whereas GalCer having hydroxy fatty acids was ineffective in modulating the PKC activity. Interestingly, all stimulators of PKC activities, including GalCer having normal fatty acids, appeared to be activators for the alpha-GalTase activity. On the other hand, GalCer having alpha-hydroxy fatty acids had no effect and ClAd was found to be a potent inhibitor for the alpha-GalTase activity. These data suggest that alpha-GalTase activity during PC12D cell differentiation may be regulated by a PKC-dependent process.
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PMID:Activation of UDP-galactose:globotriaosylceramide alpha 1-3-galactosyltransferase during PC12D cell differentiation induced by galactosylceramide. 834 95

Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to beta-nerve growth factor (beta NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factor-induced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of beta NGF or bFGF. It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetyl-cholinesterase (AChE) and SCG 10) induced by beta NGF, bFGF, EGF, and PMA, albeit in a variable fashion. There was no observed effect on the kinetics of expression as judged by TIS 8 induction by beta NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by beta NGF or bFGF. These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases.
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PMID:Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate. 846 55

The influence of activation of protein kinase C (PKC) and cyclic AMP on noradrenaline (NA) release in the neurosecretory rat pheochromocytoma PC12 cell line was investigated. External ATP induced [3H]NA release from prelabeled PC12 cells, in the presence of extracellular CaCl2. The potency order of ATP analogs was adenosine 5'-O-(gamma-thiotriphosphate) > or = ATP > 2-methylthio ATP > 2',3'-O-(4-benzoyl)benzoyl ATP. alpha,beta-Methylene ATP, beta gamma-methylene ATP, and 8-bromo ATP were inactive. Neither ADP, GTP, nor ITP was active. The addition of phorbol 12-myristate 13-acetate (PMA) or agents elevating the cyclic AMP content, such as vasoactive intestinal peptide (VIP) or an adenosine analog, also stimulated [3H]NA release. Not only high K(+)- but also ATP-stimulated [3H]NA release was enhanced by co-addition with PMA or agents elevating the cyclic AMP content. PMA and VIP had no effect on the cytosolic free Ca2+ concentration ([Ca2+]i) or on the ATP-stimulated [Ca2+]i rise, although both stimulatory effects on [3H]NA release were dependent on extracellular CaCl2. The addition of PMA stimulated [3H]NA release dose-dependently, and enhanced 300 microM (maximal dose) ATP-stimulated [3H]NA release without changing the affinity for ATP. The effect of PMA was inhibited by PKC inhibitors such as calphostin C and in PKC-depleted cells, and potentiated by elevation of cyclic AMP. These data suggest that the process of ATP-stimulated NA release, not ATP-stimulated Ca2+ influx, is regulated by the dual, PKC- and cyclic AMP-dependent mechanisms, positively and independently. Treatment with pertussis toxin had no effect on the ATP-stimulated [Ca2+]i rise or [3H]NA release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of protein kinase C and A activation on ATP-stimulated release of [3H]noradrenaline from PC12 cells. 854 66

There is strong evidence that ATP acts as an excitatory neurotransmitter in the periphery, yet little is known about fast central ATP-mediated transmission. We report here the molecular cloning of a novel neuronal ionotropic ATP receptor of the P2x subtype (P2x3) isolated from rat brain. This central P2x channel subunit has significant amino acid homology with two recently cloned ATP-gated channels from rat smooth muscle (47%) and pheochromocytoma PC12 cells (37%). P2x3 receptor contains the characteristic 10 conserved cysteines of ATP-gated channels, a putative extracellular region homologous to the Walker type A motif found in various nucleotide-binding proteins, and two potential sites for phosphorylation by protein kinase C. Homomeric receptor P2x3 channels expressed in Xenopus oocytes produce rapid cation-selective purinergic currents that are potentiated by zinc ions and reversibly blocked by the P2x antagonists suramin, Reactive Blue 2, and pyridoxalphosphate-6-axophenyl-2U,4U-disulfonic acid. P2x3-receptor subunit mRNA is found in the Purkinje cells and the granule cells of the cerebellum as well as in CA3 pyramidal cells of the hippocampus that are innervated by zinc-rich axon terminals of mossy fibers. Our results suggest that fast excitatory synaptic transmission mediated by zinc-sensitive ATP-gated channels is widespread in mammalian brain.
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PMID:A novel neuronal P2x ATP receptor ion channel with widespread distribution in the brain. 855 29

To establish whether protein kinase C was involved in the nuclear events underlying cell differentiation and proliferation, rat pheochromocytoma PC12 cells, serum-starved for 24 h, were treated with either differentiating doses of nerve growth factor or high serum concentrations, which represented a powerful mitogenic stimulus. Western blot analysis with isoform-specific antibodies, performed on whole cell homogenates, cytoplasms, and purified nuclei, showed that PKC isotypes alpha, beta I, beta II, delta, epsilon, eta, and zeta were expressed in PC12 cells and that all of them, except for beta I, were found at the nuclear level, variably modulated depending on the cell treatment. Compared to serum-stimulated cells, in which an early (1 day) and marked rise of protein kinase C activity was followed by a plateau, nerve growth factor-treated cells showed a progressive increase of protein kinase C activity coincident with the onset and maintenance of the differentiated phenotype. Western blot analysis of nuclei isolated from fully differentiated cells demonstrated an increase of protein kinase C alpha, paralleled by enhanced phosphotransferase activity along with the nerve growth factor treatment, and complete loss of the delta isotype. In contrast, in nuclei of proliferating PC12 cells, after an early but modest increase at 1 day of mitogenic stimulation, protein kinase C activity reached a plateau. Isotype-specific analysis indicated a concomitant increase of protein kinase C beta II, delta, and zeta and the appearance of protein kinase C epsilon and eta at the nuclear level. Considering the relative intensity of the cytoplasmic and nuclear immunoreactive bands under the three conditions examined, clear-cut translocation to the nucleus occurred for PKC epsilon and eta in serum-stimulated cells. Additional nuclear accumulation of PKC by translocation from the cytoplasm was prominently induced for the zeta isoform after mitogenic stimulation and for PKC alpha during prolonged NGF treatment. Our data suggest that nuclear translocation and selective activation of distinct protein kinase C isoforms play a relevant role in the control of proliferation and differentiation of the same cell type and that nuclear protein kinase C is crucial to the induction and persistence of the differentiated neuronal phenotype of PC12 cells.
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PMID:Changes of nuclear protein kinase C activity and isotype composition in PC12 cell proliferation and differentiation. 861 93

We previously reported that cross-linking surface immunoglobulin (sIg) leads to induction of the transcription factor CREB in B lymphocytes through phosphorylation at Ser133, despite the lack of an increase in cAMP. Further, cAMP-raising agents fail to induce CREB Ser133 phosphorylation and CRE-dependent gene expression in these cells, which differs sharply from the situation in PC12 rat pheochromocytoma cells where CREB responds to elevation of cAMP through the activity of protein kinase A. In this study, we characterized the signal transduction pathways leading from sIg engagement to CREB activation. By using specific inhibitors for protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), and protein kinase A (PKA), we found that anti-Ig-induced CREB Ser133 phosphorylation depends on PKC, but does not require activation of PKA or CaM kinase II. The differential responsiveness of CREB to forskolin in PC12 cells and BAL-17 B cells may relate to the more marked elevation of cAMP in the former as opposed to the latter; however, high concentrations of dbcAMP which should readily enter B cells and artificially increase cAMP levels still failed to induce CREB Ser133 phosphorylation, even in conjunction with a phosphodiesterase inhibitor. Taken together, the cAMP/PKA pathway does not appear to be as active a contributor to CREB phosphorylation in B lymphocytes as in PC12 cells, and does not appear to be involved in sIg-induced, PKC-dependent, CREB activation.
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PMID:Signaling pathways for antigen receptor-mediated induction of transcription factor CREB in B lymphocytes. 862 May 54

The regulation of catecholamine and tetrahydrobiopterin synthesis was investigated in cultured rat pheochromocytoma PC12 cells following treatments with nerve growth factor (NGF), epidermal growth factor (EGF) and interferon-gamma (IFN-gamma). NGF and EGF, but not IFN-gamma, caused an increase after 24 h in the levels of BH4 and catecholamines, and the activities of tyrosine hydroxylase and GTP cyclohydrolase, the rate-limiting enzymes in catecholamine and BH4 synthesis, respectively. Actinomycin D, a transcriptional inhibitor, blocked treatment-induced elevations in tyrosine hydroxylase and GTP cyclohydrolase activities. NGF, EGF or IFN-gamma did not affect the activity of sepiapterin reductase, the final enzyme in BH4 biosynthesis. Rp-cAMP, an inhibitor of cAMP-mediated responses, blocked the induction of tyrosine hydroxylase by NGF or EGF; inhibition of protein kinase C partially blocked the EGF effect, but not the NGF effect, NGF also induced GTP cyclohydrolase in a cAMP-dependent manner, while the EGF effect was not blocked by Rp-cAMP or protein kinase C inhibitors. Sphingosine induced GTP cyclohydrolase in a protein kinase C-independent manner without affecting tyrosine hydroxylase activity. Our results suggest that both tyrosine hydroxylase and GTP cyclohydrolase are induced in a coordinate and transcription-dependent manner by NGF and EGF, while conditions exist where the induction of tyrosine hydroxylase and GTP cyclohydrolase is not coordinately regulated.
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PMID:Regulation of tyrosine hydroxylase and tetrahydrobiopterin biosynthetic enzymes in PC12 cells by NGF, EGF and IFN-gamma. 872 83

We have previously demonstrated that neuropeptide Y (NPY) inhibits depolarization-stimulated catecholamine synthesis in rat pheochromocytoma (PC12) cells differentiated to a sympathetic neuronal phenotype with nerve growth factor (NGF). The present study uses multiple selective Ca2+ channel and protein kinase agonists and antagonists to elucidate the mechanisms by which NPY modulates catecholamine synthesis as determined by in situ measurement of DOPA production in the presence of the decarboxylase inhibitor m-hydroxybenzylhydrazine (NSD-1015). The L-type Ca2+ channel blocker nifedipine inhibited the depolarization-induced stimulation of DOPA production by approximately 90% and attenuated the inhibitory effect of NPY. In contrast, the N-type Ca2+ channel blocker omega-conotoxin GVIA inhibited neither the stimulation of DOPA production nor the effect of NPY. Antagonism of Ca2+/calmodulin-dependent protein kinase (CaM kinase) greatly inhibited the stimulation of DOPA production by depolarization and prevented the inhibitory effect of NPY, whereas alterations in the cyclic AMP-dependent protein kinase pathway modulated DOPA production but did not prevent the effect of NPY. Stimulation of Ca2+/phospholipid-dependent protein kinase (PKC) with phorbol 12-myristate 13-acetate (PMA) did not affect the basal rate of DOPA production in NGF-differentiated PC12 cells but did produce a concentration-dependent inhibition of depolarization-stimulated DOPA production. In addition, NPY did not produce further inhibition of DOPA production in the presence of PMA, and the inhibition by both PMA and NPY was attenuated by the specific PKC inhibitor chelerythrine. These results indicate that NPY inhibits Ca2+ influx through L-type voltage-gated Ca2+ channels, possibly through a PKC-mediated pathway, resulting in attenuation of the activation of CaM kinase and inhibition of depolarization-stimulated catecholamine synthesis.
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PMID:Mechanism of catecholamine synthesis inhibition by neuropeptide Y: role of Ca2+ channels and protein kinases. 875 16

Nerve growth factor (NGF) increases arachidonic acid (AA) release by PC12 pheochromocytoma cells. To explore the role of protein kinase C (PKC) in this action of NGF, PKC was down-regulated by long-term treatment of the cells with phorbol 12-myristate 13-acetate (PMA). Such prolonged exposure to PMA (1 microM) resulted in the inhibition of NGF-induced AA release. Moreover, pretreatment of PC12 cells with the protein kinase inhibitor staurosporine or with calphostin C, a specific inhibitor of PKC, also blocks the increase of AA release induced by NGF. These data, as well as that PMA alone can induce AA release in PC12 cells, suggest that PKC is necessary for NGF-induced AA release. Immunoblot analysis of whole cell lysates by using antibodies against various PKC isoforms revealed that our PC12 cells contained PKCs alpha, delta, epsilon, and zeta. PMA down-regulation depleted PKCs alpha, delta, and epsilon, and partially depleted zeta. To see which isoform was involved in NGF-induced AA release, an isoform-specific PKC inhibitor was used. GO 6976, a compound that inhibits PKCs alpha and beta specifically, blocked NGF-induced AA release. In addition, thymeleatoxin, a specific activator of PKCs alpha, beta, and gamma, induced AA release from PC12 cells in amounts comparable with those seen with NGF. Taken together, these data suggest that PKC alpha plays a role in NGF-induced AA release.
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PMID:Role of protein kinase C alpha in nerve growth factor-induced arachidonic acid release from PC12 cells. 878 12

Tyrosine hydroxylase (TH) gene transcription rate is increased in rat adrenal medulla after administration of muscarinic agonists. In order to study this muscarinic regulation of TH gene expression in more detail, we have generated a rat pheochromocytoma PC18 cell line that stably expresses the mouse m1 muscarinic acetylcholine receptor. Treatment of this cell line, designated PC18/m1-13, with carbachol leads to rapid increases in phosphatidylinositol turnover and intracellular [Ca2+]i; these increases are totally blocked by the muscarinic antagonist atropine. Carbachol produces no changes in cAMP levels or protein kinase A activity in PC18/m1-13 cells. TH mRNA levels in PC18/m1-13 cells increase approximately 3-fold after 6 h of treatment with carbachol. This induction of TH mRNA is also completely inhibited by simultaneous treatment with atropine. Transient transfection assays using a TH gene promoter-chloramphenicol acetyltransferase (TH-CAT) construct demonstrate that sequences within the most proximal 272 bp of the TH gene 5'-flanking region are responsive to carbachol in PC18/m1-13 cells. Studies using TH-CAT constructs with site-directed mutations within the TH gene promoter indicate that the responsiveness of the promoter to carbachol is mediated primarily by the cAMP response element; however, the AP1 site also participates to a lesser extent in this response. The carbachol-mediated stimulation of TH gene promoter activity is partially inhibited by down-regulation of protein kinase C (PKC) or by treatment with the Ca2+/calmodulin-dependent protein kinase inhibitor, KN62. These results are consistent with the hypothesis that agonist occupation of m1 muscarinic receptors stimulates the TH gene via signal transduction pathways that are initiated by activation of PKC and Ca2+/calmodulin-dependent protein kinase, leading to activation of transcription factors that interact with the TH CRE and AP1 sites.
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PMID:Regulation of tyrosine hydroxylase gene expression by the m1 muscarinic acetylcholine receptor in rat pheochromocytoma cells. 884 12


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