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)

Basic fibroblast growth factor (bFGF) is a well-characterized peptide hormone that has mitogenic activity for various cell types and elicits a characteristic set of responses on the cell types investigated. In this report we confirmed that bFGF is a potent mitogen for rat brain-derived oligodendrocyte (OL) precursor cells as well as for differentiated OL in secondary culture. bFGF was shown to induce expression of the protooncogene c-fos in OL. The role of protein kinase C (PKC) in mediating bFGF-stimulated proliferation as well as c-fos expression in OL was investigated. The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated c-fos expression but did not trigger cell proliferation. When PKC was down-regulated by pretreatment of OL with PMA for 20 h, the bFGF-mediated stimulations of OL proliferation and c-fos mRNA expression were still observed, whereas the induction of c-fos mRNA by PMA was totally inhibited. These data demonstrate that the bFGF mitogenic signaling pathway in OLs does not require PKC. On the other hand, bFGF was found to stimulate specifically the phosphorylation of a limited number of PKC substrates in oligodendroglial cells, including the MARCKS protein. The bFGF-dependent phosphorylation of MARCKS protein was totally inhibited when PKC was first down-regulated, indicating that the phosphorylation of this protein is PKC dependent. Tryptic digestion of the phosphorylated MARCKS protein revealed that bFGF stimulated specifically the phosphorylation of the MARCKS protein on a single phosphopeptide. We provide evidence that bFGF also stimulated fatty acylation of the MARCKS protein, which might explain the observed specific bFGF-dependent phosphorylation of this protein in OL. We propose that bFGF-dependent fatty acylation and phosphorylation of the MARCKS protein are not essential for the transduction of the bFGF mitogenic signal but are probably linked to differentiation processes elicited by bFGF on OL.
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PMID:Phosphorylation of the MARCKS protein (P87), a major protein kinase C substrate, is not an obligatory step in the mitogenic signaling pathway of basic fibroblast growth factor in rat oligodendrocytes. 130 63

The complete primary structure of a bovine-brain-derived inhibitor of protein kinase C has been established. Fragments of the purified protein were obtained by cleavage with cyanogen bromide, Staphylococcus aureus V8 protease, trypsin and chymotrypsin. Subsequent analysis of the resulting fragments by fast-atom-bombardment mass spectrometry and Edman degradation revealed a calculated molecular mass of 11,779 Da with the following 107-amino-acid sequence: [sequence: see text] This inhibitor does not share significant primary structural identity with any other known protein.
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PMID:Amino acid sequence of a 12-kDa inhibitor of protein kinase C. 191 53

The complete primary structure has been determined for an inhibitor protein of protein kinase C. The bovine brain-derived inhibitor has a pI of 6 and its N-terminal alanine residue is blocked by acetylation. Fragments obtained by chemical and enzymatic cleavage of the purified inhibitor were analyzed by Edman degradation, fast atom bombardment mass spectrometry, and tandem mass spectrometry. The results establish that the protein has a calculated average molecular mass of 13,690 daltons and contains 125 amino acid residues with the following sequence: (sequence: see text) The inhibitor does not show significant homology with any other known protein. Circular dichroism of the freshly prepared apoprotein indicated a secondary structural content of 23% alpha-helix, 31% beta-sheet, and 11% beta-turn. Immobilization on nitrocellulose followed by exposure to a 65Zn2(+)-containing overlay solution showed that, like protein kinase C itself, the inhibitor is a zinc-binding protein, although the sequence does not reveal a "zinc finger" structure. Competition with 10-fold molar excess Ca2+ or Mg2+ did not reduce the zinc-binding specificity of this inhibitor.
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PMID:Amino acid sequence and characterization of a protein inhibitor of protein kinase C. 230 77

Rapamycin and FK506 have unique cellular effects despite the fact that they bind to the same set of immunophilins, the FK506 binding proteins (FKBP). We have previously reported that rapamycin (RAP) stimulates sodium transport in A6 cells. FK506 did not stimulate sodium transport but did inhibit the stimulation seen in RAP-treated cells. Since FKBP12 has been shown to have sequence homology with an endogenous inhibitor of protein kinase C (PKC) and PKC inhibition has been shown to increase Na+ channel activity in A6 cells, studies to determine the effect of RAP on PKC activity and its relationship to sodium transport were performed. Here we report that RAP stimulates sodium transport, and the effect is not additive to that seen with a cell-permeant inhibitor of PKCalpha and -beta subtypes. RAP significantly inhibits endogenous PKC activity in A6 cells both in membrane and cytosolic preparations. There is a strong correlation between the degree of inhibition of PKC activity and the stimulation of sodium transport by RAP. RAP has no effect on Na+/K+-ATPase activity over this time course. Purified recombinant FKBP12 with or without FK506 has no effect on PKC activity when incubated with a rat brain-derived PKC preparation of known activity. By contrast, RAP plus FKBP12 significantly inhibits PKC activity. RAP plus FKBP12 inhibits the PKCalpha and not the -beta subtype. The results demonstrate inhibition of PKC activity by RAP and not FK506 through its binding to FKBP12. The inhibition of PKC activity by RAP stimulates sodium transport in A6. The results therefore imply the existence of an endogenous RAP-like ligand which when bound to FKBP12 could regulate Na+ channel activity through this mechanism.
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PMID:Rapamycin inhibits protein kinase C activity and stimulates Na+ transport in A6 cells. 894 13

The brain-derived peptide preparation Cerebrolysin (C1; EBEWE, Austria) increases the stability of blood-brain barrier (BBB)-GLUT1 transcript. To determine if the increase in BBB-GLUT1 mRNA stability is associated with an augmentation of gene expression, the present investigation studied the effect of C1 on the expression of a BBB-GLUT1-luciferase reporter gene in brain endothelial cultured (ECL) cells. Dose response studies showed that C1 markedly increased the expression of luciferase when the BBB-GLUT1-reporter gene was used. On the contrary, C1 produced no changes in the expression pattern of the control reporter gene, which lacks the GLUT1 regulatory sequence. Desensitization of the protein kinase C (PKC) receptor with the phorbol ester TPA, or inhibition with either 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) or staurosporine, had no effect on the increased levels of luciferase induced by C1. Transfection efficiency was determined by measuring intracellular levels of the expression vector using a quantitative polymerase chain reaction (PCR) assay. The data presented here demonstrate that C1 increases BBB-GLUT1 gene expression in ECL cells through a mechanism that appears to be independent of activation of PKC.
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PMID:Brain-derived peptides increase the expression of a blood-brain barrier GLUT1 glucose transporter reporter gene. 897 47

VP 4-8 as a highly potent behavioral-active metabolite of arginine-vasopressin (VP) has been studied in detail at four levels, i.e. ligand level, membrane binding level, intracellular level and nuclear level. The purpose of this chapter is to review and discuss the main results obtained from our recent pharmacological and biochemical investigations which are described as follows: 1, structure-function relationship of VP 4-8 and its analogs; 2, some characters of VP 4-8-specific binding, the distribution of the binding sites in the rat brain and the consequent effect on long-term potentiation of synaptic transmission; 3, a putative receptor-mediated signaling pathway involving second messenger IP3, immediately-early gene c-fos transcription and protein kinase PKC, CaMKII and MAPK; 4, peptide-induced enhancement of some crucial functional proteins such as calmodulin, nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF). The physiological significance of the events following VP 4-8 administration and particularly, its possible role in learning and memory processes are discussed.
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PMID:Function and molecular basis of action of vasopressin 4-8 and its analogues in rat brain. 1007 88

This study characterizes and examines the P2 receptor-mediated signal transduction pathway of a rat brain-derived type 2 astrocyte cell line, RBA-2. ATP induced Ca2+ influx and activated phospholipase D (PLD). The ATP-stimulated Ca2+ influx was inhibited by pretreating cells with P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), in a concentration-dependent manner. The agonist 2'- and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) stimulated the largest increases in intracellular Ca2+ concentrations ([Ca2+]i); ATP, 2-methylthioadenosine triphosphate tetrasodium, and ATPgammaS were much less effective, whereas UTP, ADP, alpha,beta-methylene-ATP, and beta,gamma-methylene-ATP were ineffective. Furthermore, removal of extracellular Mg2+ enhanced the ATP- and BzATP-stimulated increases in [Ca2+]i. BzATP stimulated PLD in a concentration- and time-dependent manner that could be abolished by removal of extracellular Ca2+ and was inhibited by suramin, PPADS, and oxidized ATP. In addition, PLD activities were activated by the Ca2+ mobilization agent, ionomycin, in an extracellular Ca2+ concentration-dependent manner. Both staurosporine and prolonged phorbol ester treatment inhibited BzATP-stimulated PLD activity. Taken together, these data indicate that activation of the P2X7 receptors induces Ca2+ influx and stimulates a Ca2+-dependent PLD in RBA-2 astrocytes. Furthermore, protein kinase C regulates this PLD.
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PMID:ATP-stimulated Ca2+ influx and phospholipase D activities of a rat brain-derived type-2 astrocyte cell line, RBA-2, are mediated through P2X7 receptors. 1038 86

The effects of endothelin-1 (ET-1) on the production of plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) by human brain-derived endothelial cells in culture were studied. At 100 nmol/L, ET-1 increased PAI-1 production by 88+/-6% within 72 hours, and increased PAI-1 mRNA expression within 1 hour of stimulation; there was no significant effect on t-PA production. PAI-1 activity was also examined and found to increase with ET-1 treatment. Suboptimal concentrations of ET-1 and tumor necrosis factor-alpha (TNF-alpha) acted synergistically to increase PAI-1 production. ET-1 activated protein kinase C and cAMP-dependent protein kinase pathways within 3 to 5 minutes of treatment, with the peak at 10 minutes. Activation of protein kinase C by phorbol-12-myristate-13-acetate (PMA) resulted in increased PAI-1 production, whereas activation of the cAMP-dependent protein kinase by forskolin or dibutyryl cAMP (dBu-cAMP) significantly decreased PAI-1 production. However, simultaneous activation of protein kinase C by PMA and cAMP-dependent protein kinase by dBu-cAMP only slightly attenuated PMA-induced PAI-1 increase. Inhibition of protein kinase C by GF-109213X abolished the effects of ET-1. These results demonstrate that ET-1 and TNF-alpha function synergistically to induce procoagulant activity of brain endothelial cells in a process that involves a protein kinase C-dependent pathway.
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PMID:Endothelin-1 enhances plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-dependent pathway. 1039 97

Munc18-1 is a mammalian member of the SEC1 protein family implicated in neuronal secretion. Its sequence contains several consensus sites for phosphorylation by protein kinase C (PKC), a kinase known to enhance secretion. We have characterized the phosphorylation of the synaptic munc18-1 pool by endogenous, presynaptic PKC-isoforms. In isolated rat brain nerve terminals, munc18-1 was almost completely nonphosphorylated. Its phosphorylation state increased by 250% on inhibition of endogenous phosphatases and by 1500% on additional, direct PKC activation using phorbol esters. K+-evoked depolarization also increased munc18-1 phosphorylation, by 50% within 5 s in a Ca2+-dependent manner. Munc18-1 phosphorylation in nerve terminals was blocked by PKC inhibitors. Activation of endogenous PKC in nerve terminals inhibited the interaction of synaptic munc18-1 with its binding partner syntaxin-1A by 50%. Munc18-1 antisera precipitated 80% of native, brain-derived munc18-1 from salt solutions, but only 12% from synaptosomal lysates, together with 6% synaptic syntaxin-1A/B; these amounts were not changed by PKC activation. In this 12%, the phosphate incorporation per mole of munc18 was four-fold lower than the total pool. We conclude that the synaptic munc18-1 pool can be readily and rapidly phosphorylated by endogenous presynaptic PKC isoforms. A high constitutive phosphatase activity keeps its basal phosphorylation state low so that PKC activation can increase the phosphorylation state dramatically. These phosphorylation dynamics and the effects on the interaction with syntaxin-1A make munc18-1 a prominent candidate to account for PKC-dependent enhancement of secretion.
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PMID:Dynamics of munc18-1 phosphorylation/dephosphorylation in rat brain nerve terminals. 1065 95

Brain tissue damage due to ischemia/reperfusion has been shown to be caused, in part, by activated macrophages infiltrating into the post-ischemic brain. Using the Middle Cerebral Artery Occlusion (MCAO) mouse model, this study demonstrated that, in vivo, both endothelin-1 (Et-1), a potent vasoconstrictor, and the macrophage chemokine, monocyte chemoattractant factor-1 (MCP-1) are induced in ischemia. Further studies, using human brain-derived endothelial cells (CNS-EC), showed that in vitro, Et-1 can directly stimulate MCP-1 mRNA expression and MCP-1 protein; and this Et-1-induced MCP-1 production is mediated by the ET(A) receptor. Inflammatory cytokines, tumor necrosis factor alpha and interleukin-1beta, functioned additively and synergistically, respectively, with Et-1 to increase this MCP-1 production. Partial elucidation of the signal transduction pathways involved in Et-1-induced MCP-1 production demonstrated that protein kinase C-, but not cAMP-dependent pathways are involved. These data demonstrate that Et-1, functioning as an inflammatory peptide, increased levels of MCP-1, suggesting a mechanism for chemokine regulation during ischemia/reperfusion injury.
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PMID:Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures. 1131 31


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