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)

A brief high frequency tetanic stimulation of afferent fibers induces a long-term potentiation (LTP) of synaptic transmission, which is manifested by an increase in the size of the synaptic response elicited by low frequency stimulation of the same synapse. LTP persists for several hours in vitro and up to several weeks in vivo, and is at present the most extensively studied form of activity-dependent synaptic plasticity. This article focuses on the relationship between two key elements in the induction of LTP--the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the Ca(2+)-phospholipid-dependent protein kinase C (PKC). In view of several recent findings that describe a direct positive modulation of NMDA currents by PKC, we suggest that PKC activity may, in fact, determine the threshold of LTP induction. Enhanced kinase activity may underlie the central role of the NMDA receptor--channel complex in neuronal plasticity.
Trends Neurosci 1992 Sep
PMID:Protein kinase C modulation of NMDA currents: an important link for LTP induction. 138 31

In A-431 cells, platelet-activating factor (PAF) induces the expression of c-fos and TIS-1 genes in both the absence and the presence of cycloheximide in a structurally specific and receptor-coupled manner. We have now investigated the molecular mechanisms of this response, particularly in relation to the role of protein kinases. Pretreatment of cells with genistein or methyl-2,5-dihydroxycinnamate (tyrosine kinase inhibitors) or staurosporine (a protein kinase C inhibitor) for 20 min abolished the c-fos expression induced by PAF. Interestingly, when genistein was added 90 s after addition of PAF, no inhibition was observed. Similarly, staurosporine did not inhibit c-fos expression when added 8 min after PAF addition to the cells. These inhibitions were dose-dependent (IC50 for staurosporine was 180 nM, and for genistein 50 microM). Simultaneous addition of PAF and phorbol 12-myristate 13-acetate (PMA) did not give a synergistic effect on c-fos expression. Pretreatment of cells with PMA had no effect on [3H]PAF binding, but abolished the PAF-induced gene expression. PAF-stimulated gene expression was desensitized if cells were pretreated with PAF. Interestingly, epidermal growth factor was able to stimulate c-fos expression in PAF-desensitized cells, and thus indicated involvement of distinct mechanisms for the two stimuli. Forskolin, an activator of adenylate cyclase, did not induce c-fos expression and had no effect on the PAF response. Exposure of cells to PAF for as little as 1 min, followed by its removal, was sufficient to activate the gene expression and demonstrated the rapidity and the exquisite nature of the signalling involved in this process. It is concluded that activation of PAF receptor (a proposed G-protein-coupled receptor) causes rapid production of signals which induce the expression of c-fos gene and that this is mediated via tyrosine kinase and protein kinase C.
Biochem J 1992 Sep 01
PMID:Involvement of tyrosine kinase and protein kinase C in platelet-activating-factor-induced c-fos gene expression in A-431 cells. 138 9

Protein tyrosine kinase (PTK) blockers (tyrphostins) inhibit in a dose-dependent fashion thrombin-induced aggregation and serotonin release with IC50 values in the 10-35 microM concentration range. The inhibition of thrombin-induced aggregation correlates with their potency in inhibiting phosphorylation of proteins on tyrosine residues. Using metabolically 32P-labelled human platelets, it was found that the tyrphostins have no effect on the decrease in [32P]phosphatidylinositol bisphosphate but prevent the replenishment of [32P]polyphosphoinositide. Tyrphostins decreased [32P]phosphatidic acid production induced by thrombin, although never by more than 50%, and only delayed the peak of diacylglycerol, suggesting that phospholipase C was still activated. Tyrphostins inhibited the thrombin-elicited early phosphorylation of p43 and p20, substrates for protein kinase C (PKC) and myosin light chain kinase, respectively, at short times of activation. This inhibition, however, was overcome after 1 min of stimulation with thrombin. Tyrphostin AG213 also inhibited platelet aggregation and tyrosine protein phosphorylation induced by phorbol myristate acetate (PMA), but did not inhibit pleckstrin phosphorylation. These results suggest that thrombin induces the phosphorylation of proteins on tyrosine residues which most probably results in the activation of phosphoinositide kinases. The ability of tyrphostins to inhibit phosphorylation of p43 and p20 when induced by thrombin but not when induced by PMA confirms that PTKs may be involved subsequent to PKC activation.
Biochem Pharmacol 1992 Sep 01
PMID:Inhibition of platelet activation by tyrosine kinase inhibitors. 138 25

Two human homologues of protein kinase C-epsilon (E1 and E2) were isolated from two distinct cDNA libraries. Sequence comparisons to PKC-epsilon cDNAs from several species indicated that each of these human epsilon clones contained cloning artifacts. Thus, a composite PKC-epsilon (E3) clone was derived from clones E1 and E2. Human PKC-epsilon (E3) has an overall sequence identity of 90-92% at the nucleotide level compared to the previously characterized mouse, rat and rabbit clones. At the amino acid level, the deduced human epsilon sequence shows a 98-99% identity with the mouse, rat and rabbit sequences. Expression of the human PKC-epsilon clone in Sf9 cells confirmed that the recombinant protein displayed protein kinase C activity and phorbol ester binding activity. The recombinant protein was also recognized by two distinct epsilon-specific polyclonal antibodies.
Biochim Biophys Acta 1992 Sep 24
PMID:Sequence and expression of human protein kinase C-epsilon. 138 5

Upon stimulation by various ligands, freshly isolated human peripheral neutrophils (PMN) respond in a variety of ways, such as superoxide (O2-.) generation, phagocytosis enzyme release, migration etc. Chemotactic peptide formylmethionyl-leucyl-phenylalanine (FMLP) and opsonized zymosan activate neutrophils by a receptor-mediated mechanism, while phorbol myristate acetate and dioctanoylglycerol activate the cells by a mechanism involving Ca(2+)-and phospholipid-dependent protein kinase (PKC). Receptor-mediated but not PKC-mediated O2-. generation in PMN was enhanced by the priming of recombinant human granulocyte colony stimulating factor (G-CSF). FMLP-dependent luminol chemiluminescence was also enhanced by G-CSF. However, no appreciable enhancement was observed in FMLP-induced intracellular calcium ion concentration ([Ca2+]i). Enhancement of FMLP-induced generation of O2-. by G-CSF was inhibited by genistein or alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide (ST 638), inhibitors of tyrosine kinase (TK), and was stimulated by staurosporine and 1-(5-isoquinolinesulfonyl)-3-methyl-piperazine (H-7), inhibitors of PKC. The ED50 values of genistein and ST 638 for the inhibition of the FMLP-induced O2-. generation from G-CSF were 0.5 and 5 microM, respectively. In contrast, O2-. generation by PKC activation without G-CSF priming was inhibited by stauroporine and H-7, but was stimulated by genistein and ST 638. These results suggested that the enhancing effect of G-CSF on receptor-mediated generation of the O2-. might be regulated by protein kinases, such as TK and PKC, and that the TK inhibitor selectively inhibited the G-CSF-primed receptor-mediated O2-. generation of neutrophils.
Biochem Pharmacol 1992 Sep 25
PMID:Neutrophil priming by granulocyte colony stimulating factor and its modulation by protein kinase inhibitors. 138 97

The N-methyl-D-aspartate (NMDA) receptor of rat cerebellar granule cells in primary culture is inhibited by phospholipase C-coupled receptor activation. In the absence of ionotropic agonist, cells modulate their cytoplasmic free Ca2+, [Ca2+]c, in response to stimulation of M3 muscarinic receptors, metabotropic glutamate receptors, and endothelin receptors by the respective agonists carbachol, trans-1-amino-1,3-cyclopentanedicarboxylic acid, and endothelin-1. The response is consistent with the ability of phospholipase C-coupled receptors to release a pool of intracellular Ca2+ and induce a subsequent Ca2+ entry into the cell; both of these responses can be abolished by discharge of internal Ca2+ stores with low concentrations of ionomycin or thapsigargin. In the case of cells stimulated with NMDA, the [Ca2+]c response to the phospholipase C-coupled agonists is complex and agonist dependent; however, in the presence of ionomycin each agonist produces a partial inhibition of the NMDA component of the [Ca2+]c signal. This inhibition can be mimicked by the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate. It is concluded that NMDA receptors on cerebellar granule cells are inhibited by phospholipase C-coupled muscarinic M3, glutamatergic, and endothelin receptors via activation of protein kinase C.
J Neurochem 1992 Sep
PMID:Interactions between phospholipase C-coupled and N-methyl-D-aspartate receptors in cultured cerebellar granule cells: protein kinase C mediated inhibition of N-methyl-D-aspartate responses. 138 23

Annexin I (AnxI) contains phosphorylation sites in its "hinge region" that have been implicated in the regulation of cell growth and/or differentiation. A pigeon (Columba livia) isoform of this protein, annexin Icp35 (cp35), has a very similar amino acid sequence overall but an unrelated sequence that lacks phosphorylation sites in the hinge region. We now report the identification and characterization of annexin Icp37 (cp37) from pigeon. Genomic cloning and Southern blot analysis demonstrated that cp37 and cp35 were encoded by separated genes. Prolactin induced the expression of cp35 mRNA but not cp37. The amino acid sequence of cp37 was deduced from a cDNA clone and found to share 93 and 75% sequence identity with cp35 and human AnxI, respectively. The amino acid sequence of cp37 bore similarities to both AnxI and cp35 in the critical hinge region. Like AnxI, cp37 contained consensus phosphorylation sites in its amino acid sequence and was phosphorylated on tyrosine by the EGF receptor/kinase and on serine by protein kinase C in vitro. Despite the functional similarities between cp37 and AnxI, the nucleotide sequence that encoded the hinge region of cp37 was very similar to the analogous region of cp35, but different from that of AnxI. We propose that certain features shared by cp37 and AnxI are the products of convergent evolution. The fact that evolution independently selected for two annexin I-like genes (cp37 and anxI) encoding analogous phosphorylation sites is strong evidence that phosphorylation is important for the regulation of the biological activity of these proteins.
J Biol Chem 1992 Sep 25
PMID:Identification and characterization of columbid annexin Icp37. Insights into the evolution of annexin I phosphorylation sites. 138 65

A large number of PKC inhibitors are positively charged. We evaluated the structural features of cationic amphiphiles which are necessary for inhibiting PKC. Many of these compounds were derivatives of cholesterol, which possesses a hydrophobic backbone which does not perturb hydrocarbon packing in membrane bilayers. In addition, they contain a tertiary or quaternary nitrogen functionality in the head group. All designed cholesterol-based amphiphiles inhibit PKC activity; the potency of the amphiphile correlates with the presence of positive charge. Quaternary ammonium amphiphiles are 10-fold more potent than their tertiary amine counterparts, generally inhibiting in the 10-60 microM range using the Triton mixed micelle assay. Aside from charge, factors such as the structure of the amine-containing head group, its length from the hydrocarbon moiety, or the number of amine groups on the amphiphile did not markedly influence inhibitor potency. In contrast, the hydrocarbon backbone did influence potency: cationic amphiphiles containing a steroid backbone were more potent inhibitors of PKC than their straight-chain analogues. Changing the nature of the hydrocarbon from a sterol to an alkyl group lowers the pK of the amine head group so that the straight-chain analogues are no longer cationic in the conditions in the PKC assay. The results of these studies suggest that a combination of positive charge and a bilayer-stabilizing structural characteristic provides a basis for the rational design of PKC inhibitors.
Biochemistry 1992 Sep 22
PMID:Inhibition of protein kinase C by cationic amphiphiles. 139 Jun 89

Magnetic fields are physical, environmental agents that have been shown to produce a variety of responses in cellular and animal studies, including general changes in gene transcription. In this study, the nuclear run-off assay has been employed to assess alterations in specific gene transcription in CEM-CM3 T-lymphoblastoid cells exposed for 15-120 min to a 1 gauss sinusoidal magnetic field at 60 Hz. Time-dependent and cell density-dependent changes in the transcription of c-fos, c-jun, c-myc and protein kinase C (beta-form) have been observed and quantitated. Additionally, changes in transcript levels, assessed by slot-blot analysis, have been found to parallel the changes in gene transcription. These data suggest an important role for magnetic field exposure in altering cellular processes.
Biochim Biophys Acta 1992 Sep 24
PMID:Magnetic field-induced changes in specific gene transcription. 139 Aug 86

The tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a strong activator of protein kinase C (PKC) and okadaic acid, which is ineffective in this respect, induce a rapidly developing ('early') edema of the mouse ear. Bryostatin, another potent activator of PKC, is unable to induce an 'early' edema but causes a more delayed development of edema at a time when most of the PKC is down-regulated. The PKC inhibitor staurosporine neither inhibits the early TPA- nor the late bryostatin-induced edema, but suppresses the okadaic acid-induced edema very effectively. TPA as well as bryostatin, but not okadaic acid cause a down-regulation of PKC, which is not inhibited by staurosporine. The calmodulin antagonist cyclosporine A, which does not suppress PKC activity, very effectively inhibits the TPA-induced edema and down regulation of PKC. Hence we conclude that protein phosphorylation catalyzed by staurosporine-suppressable PKC is not involved in the induction of edema and PKC down-regulation by TPA but that a calmodulin dependent process may play a critical role in these and other TPA effects in mouse skin.
Cancer Lett 1992 Sep 30
PMID:Differential inhibition by staurosporine of phorbol ester, bryostatin and okadaic acid effects on mouse skin. 139 18


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