Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate an interaction between vasoconstrictive (Ang II) and vasodilating (ANP) peptides, we examined the effect of Ang II on ANP-induced accumulation of cGMP in cultured glomerular mesangial cells. ANP rapidly increased intracellular cGMP levels, with a peak stimulation at one minute in the absence of IBMX and at ten minutes in the presence of IBMX. The ANP-induced cGMP accumulation was significantly inhibited when the cells were treated with Ang II simultaneously with ANP for one minute in the absence of IBMX. This inhibitory effect of Ang II was completely abolished by IBMX and significantly reduced in calcium-free media or by W7, but not affected by H7. Similar inhibitory effect was observed when cells were treated with A23187 but not with TPA for one minute. In the presence of IBMX, Ang II inhibited ANP-induced cGMP accumulation when cells were treated with Ang II for 15 minutes prior to the stimulation by ANP. This inhibition by Ang II was blocked by H7. ANP-induced increase in particulate guanylate cyclase activity was significantly reduced in the cells treated with Ang II or TPA. This reduction of enzyme activity was also prevented by H7. These results indicate that Ang II inhibits ANP-induced cGMP accumulation in cultured glomerular mesangial cells through at least two mechanisms; one is the activation of calcium-dependent, calmodulin-stimulated cyclic nucleotide phosphodiesterase in the initial phase, and the other is the inhibition of guanylate cyclase resulting from protein kinase C activation in the maintenance phase.
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PMID:Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation. 171 65

Glomerular mesangial cells are believed to contribute to regulation of glomerular filtration rate through their contractility, which is regulated by various vasoactive hormones such as angiotensin II (A II), and atrial natriuretic peptide (ANP). A II has been recently reported to inhibit ANP-induced cyclic GMP (cGMP) accumulation in vascular smooth muscle cells, and other types of cells, but the mechanism of this inhibitory effect of A II is still unclear. In order to know the interaction between A II and ANP in glomerular mesangial cells and to know the mechanism of the interaction, I examined the effects of A II on ANP-induced cGMP accumulation in cultured rat glomerular mesangial cells. ANP produced rapid increase in cellular cGMP in cultured rat glomerular mesangial cells, which was significantly inhibited by co-incubation with A II. A II also inhibited cGMP accumulation produced by sodium nitroprusside, soluble guanylate cyclase activator. This inhibitory effect of A II was completely blocked by 1 mM of 3-isobutyl-1-methylxanthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor. Thus, it seems that A II inhibits ANP-induced cGMP accumulation by activating phosphodiesterase rather than by inhibiting guanylate cyclase. Since the action of A II has been reported to be mediated by increase of cytosolic free Ca2+ secondary to inositol 1,4,5-trisphosphate (IP3) generation and activation of protein kinase C secondary to diacylglycerol (DG) generation, I investigated the effects of Ca ionophore (A23187), and 12-O-tetradecanoyl phorbol-13-acetate (TPA), protein kinase C activator, on ANP-induced cGMP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Angiotensin II decreases atrial natriuretic peptide-induced cyclic GMP accumulation in rat glomerular mesangial cells]. 216 60

Racemic gossypol has been shown to have antitumor properties that may be due to its ability to uncouple tumor mitochondria or to its inhibitory effects on a variety of nonmitochondrial enzymes. We have studied the antimitochondrial and enzyme-inhibiting properties of gossypol in human carcinoma cell lines of breast (MCF-7, T47-D), ovarian (OVCAR-3) colon (HCT-8), and pancreatic (MiaPaCa) origin by comparing the effects of its purified (+)- and (-)-enantiomers. (-)-Gossypol shows up to 10-fold greater antiproliferative activity than (+)-gossypol in the cancer cell lines and in normal hematopoietic stem cells grown in vitro, with IC50 values ranging from 1.5 to 4.0 microM for the cancer cells and from 10 to 20 microM for the human marrow stem cells. As well, multidrug-resistant MCF/Adr cells appear more resistant to (-)-gossypol than their parental cell line. Electron microscopy indicates that the earliest ultrastructural change in tumor cells exposed to a cytotoxic (10 microM) concentration of (-)-gossypol is the selective destruction of their mitochondria. Consistent with this observation, 31P magnetic resonance spectroscopy detects pronounced changes in tumor cell high energy phosphate metabolism within 24 hr of (-)-gossypol treatment, manifest by 1.6- to greater than 50-fold differential reductions in the intracellular ratios of ATP/Pi, relative to (+)-gossypol-treated cell lines; the magnitude of these antimitochondrial effects correlates with the antiproliferative activity of (-)-gossypol. Northern blot RNA analyses suggest that treatment with a 5-10 microM dose of (-)-gossypol induces a transient increase in the expression of heat shock gene products, particularly hsp-70 transcripts. The mean 5-fold increase in (-)-gossypol-induced hsp-70 mRNA appears coincident with a comparable heat-stimulated increase in transcript levels, as compared with control or (+)-gossypol-treated cells. The enzyme-inhibiting properties of gossypol enantiomers were compared in cell-free assays measuring glutathione-S-transferase-alpha, -mu, and pi activities, calmodulin stimulation of cyclic nucleotide phosphodiesterase, and protein kinase C activity. Both enantiomers are near equivalent antagonists of calmodulin stimulation and protein kinase C activity, exceeding the potency of known inhibitors such as phenothiazines by as much as 50-fold. In contrast, (-)-gossypol is a 3-fold more potent inhibitor of glutathione-S-transferase-alpha and -pi isozyme activity, resulting in IC50 values of 1.6 and 7.0 microM, respectively, for these two isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers. 219 25

The interaction between prostaglandin E1 (PGE1) and chemotactic peptide formylmethionyl-leucyl-phenylalanine (fMLP) in cAMP production in guinea pig neutrophils was investigated. Both PGE1 and fMLP increased the cAMP content in neutrophils. At low concentrations of PGE1 (less than 10 nM), the effects of fMLP and PGE1 in stimulating cAMP accumulation were additive, but at high concentrations of PGE1, their effects were synergistic. The effects of PGE1 and Ca2+ ionophore A23187 instead of fMLP on cAMP accumulation were also synergistic. The synergy did not appear to be related to change in cyclic nucleotide phosphodiesterase activity, because it was still marked in the presence of isobutyl-3-methyl-1-xanthine, a phosphodiesterase inhibitor. Studies on the time course of PGE1-induced cAMP accumulation showed that cAMP production ceased within 5 min after the addition of high concentrations of PGE1. The period of cAMP production could not be prolonged by combined treatment with PGE1 and fMLP or Ca2+ ionophore A23187. The synergy was found to be caused through Ca2+-dependent processes, because depletion of the medium of Ca2+ and addition of the Ca2+ antagonist TMB-8 inhibited the synergistic increase in cAMP. Moreover, the calmodulin antagonist W-7 also effectively inhibited the synergistic increase in cAMP. These results suggest that the potentiation of PGE1-induced cAMP production by fMLP or Ca2+ ionophore A23187 is catalyzed by calmodulin-dependent processes. However, the synergistic increase in cAMP production was not inhibited by arachidonic acid cascade inhibitors such as indomethacin, BW755C, or nordihydroguiaretic acid, and a combination of PGE1 and a protein kinase C activator, tetradecanoyl phorbol acetate (TPA), did not cause synergistic increase in cAMP. Marked increase in cAMP was also induced by a combination of cholera toxin and fMLP or Ca2+ ionophore A23187, but not by a combination of forskolin and fMLP or Ca2+ ionophore A23187. The synergistic increase in cAMP was not sustained in isolated membranes. On the contrary, PGE1-induced cAMP production in isolated membranes was suppressed by their pretreatment with fMLP or Ca2+ ionophore A23187. These data suggest that the synergistic effects of PGE1 and fMLP or Ca2+ ionophore in increasing the cAMP level are due to potentiation of PGE1-induced cAMP production by Ca2+ and calmodulin-dependent processes.
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PMID:Potentiation of PGE1-induced increase in cyclic AMP by chemotactic peptide and Ca2+ ionophore through calmodulin-dependent processes. 243 45

Mitogenic effects of agents activating either the protein kinase C (PDGF; phorbol esters) or the insulin-like growth factor 1 (IGF1)-receptor pathway were studied in quiescent chemically transformed mouse fibroblasts (BP-A31), by evaluating the rate of [3H]thymidine incorporation. Each of these pathways alone was found to be sufficient to sustain progression through the entire cell division cycle. The mitogenic activity of phorbol 12-myristate 13-acetate (PMA) but not that of insulin was blocked by staurosporine (an inhibitor of protein kinase C), in support of the notion that protein kinase C activation was required for the PMA-induced cell cycle progression. The mitogenic effects of PMA were potentiated by cycloheximide pretreatment, and they were abolished by 3-isobutyl-1-methyl xanthine (IBMX; a cyclic nucleotide phosphodiesterase inhibitor). PDGF (known to activate the phospholipase C-protein kinase C pathway) also displayed mitogenic activity in the cycloheximide-pretreated BP-A31 cells, and its effects were prevented by IBMX. In contrast, the mitogenic effects of insulin (at concentrations where it activates the IGF1 receptor) or of IGF1 neither were notably influenced by cycloheximide pretreatment nor were inhibited by IBMX (in the presence of IBMX, the onset of S-phase was delayed by several hours). The expression of the c-fos gene was absent at quiescence; its induction by growth factors was not proportional to their mitogenic potency. Thus, c-fos expression was strongly induced by PMA but only weakly by insulin. IBMX was a powerful inducer of c-fos gene expression but caused a decrease in the level of c-myc mRNA.
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PMID:Mitogenic activity of phorbol esters and insulin-like growth factor 1 in chemically transformed mouse fibroblasts BP-A31: independent effects and differential sensitivity to inhibition by 3-isobutyl-1-methyl xanthine. 246 95

We have evaluated the possibility that a major, abundant cellular substrate for protein kinase C might be a calmodulin-binding protein. We have recently labeled this protein, which migrates on sodium dodecyl sulfate-gel electrophoresis with an apparent Mr of 60,000 from chicken and 80,000-87,000 from bovine cells and tissues, the myristoylated alanine-rich C kinase substrate (MARCKS). The MARCKS proteins from both species could be cross-linked to 125I-calmodulin in a Ca2+-dependent manner. Phosphorylation of either protein by protein kinase C prevented 125I-calmodulin binding and cross-linking, suggesting that the calmodulin-binding domain might be located at or near the sites of protein kinase C phosphorylation. Both bovine and chicken MARCKS proteins contain an identical 25-amino acid domain that contains all 4 of the serine residues phosphorylated by protein kinase C in vitro. In addition, this domain is similar in sequence and structure to previously described calmodulin-binding domains. A synthetic peptide corresponding to this domain inhibited calmodulin binding to the MARCKS protein and also could be cross-linked to 125I-calmodulin in a calcium-dependent manner. In addition, protein kinase C-dependent phosphorylation of the synthetic peptide inhibited its binding and cross-linking to 125I-calmodulin. The peptide bound to fluorescently labeled 5-dimethylaminonaphthalene-1-sulfonyl-calmodulin with a dissociation constant of 2.8 nM, and inhibited the calmodulin-dependent activation of cyclic nucleotide phosphodiesterase with an IC50 of 4.8 nM. Thus, the peptide mimics the calmodulin-binding properties of the MARCKS protein and probably represents its calmodulin-binding domain. Phosphorylation of these abundant, high affinity calmodulin-binding proteins by protein kinase C in intact cells could cause displacement of bound calmodulin, perhaps leading to activation of Ca2+-calmodulin-dependent processes.
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PMID:Phosphorylation-regulated calmodulin binding to a prominent cellular substrate for protein kinase C. 255 40

The inhibitory effects of sulfasalazine, some sulfasalazine-related compounds and indomethacin on superoxide production by human polymorphonuclear (PMN) leukocytes were studied. The inhibition of the chemotactic peptide (FMLP)-induced superoxide production, which is membrane receptor-mediated, was strongly dependent on the concentration both of the secretory stimulus and of the test compounds, indicating an interaction between the receptor and the test compound. Furthermore, a positive correlation was found between the lipophilicity of the compound and the degree of inhibition. However, when the receptor was by-passed by direct activation of the receptor-linked G protein by the use of fluoride ions as secretory stimuli, the test compounds still inhibited superoxide production. On the other hand, superoxide production by cells stimulated with phorbol ester was not inhibited by the test compounds. Furthermore, the production of phosphatidic acid was decreased in the presence of sulfasalazine, indicating impaired phosphoinositide metabolism. The inhibition of this metabolism was not due to increased intracellular concentrations of cyclic AMP, although sulfasalazine did inhibit cyclic nucleotide phosphodiesterase. We conclude that sulfasalazine attenuates superoxide production by PMN leukocytes at a post-receptor site of action at a step before the activation of protein kinase C, possibly by interfering with the phosphoinositide metabolism but independent of cyclic AMP.
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PMID:Inhibitory effects of sulfasalazine and related compounds on superoxide production by human polymorphonuclear leukocytes. 257 51

Felodipine, a dihydropyridine Ca2+ channel blocker, appears to have intracellular sites of action in addition to its ability to attenuate voltage-dependent Ca2+ channels in smooth muscle cells. In vitro, felodipine inhibits several calmodulin-dependent enzymes such as myosin light chain kinase, cyclic nucleotide phosphodiesterase and caldesmon kinase [Walsh MP, Sutherland C and Scott-Woo GC, Biochem Pharmacol 37: 1569-1580, 1988]. Such effects may partially explain the relaxant effects of felodipine and related dihydropyridines on vascular smooth muscle. We have examined the effects of felodipine on the activity of another important enzyme which has been implicated in the regulation of the contractile state of smooth muscle, protein kinase C. We chose to use a physiologically relevant substrate of protein kinase C for these studies, viz. platelet P47 protein, rather than the more commonly used lysine-rich histone which is probably not a physiologically important substrate. Protein kinase C and P47 were purified from human platelets and their important structural and functional properties were characterized. Felodipine and the p-chloro analogue of felodipine enhanced both the rate and extent of P47 phosphorylation by protein kinase C. Half-maximal activation was observed at 9.5 microM felodipine and 8.5 microM p-chloro analogue. Activation by felodipine was dependent upon the presence of phospholipid but did not require diacylglycerol. These observations suggest that the pharmacological actions of felodipine and related dihydropyridines may involve activation of protein kinase C in addition to their known effects on voltage-dependent Ca2+ channels and calmodulin-dependent enzymes.
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PMID:Activation of protein kinase C by the dihydropyridine calcium channel blocker, felodipine. 270 18

Cyclic GMP depresses Ba2+ current through high-voltage-activated Ca2+ channels (ICa) in acutely isolated hippocampal neurons. The effect is produced by intra-, but not extracellular, cGMP or by 5' GMP. The membrane-permeant derivative, 8-Br-cGMP, produces a reversible suppression. The effect of 8-Br-cGMP is similar to phorbol ester-induced ICa depression, except that ICa depression due to 8-Br-cGMP is not blocked by protein kinase inhibitors H-8 or H-7, whereas phorbol ester effects are. The data suggest that cGMP depresses ICa by a cGMP-kinase- and protein kinase C (PKC)-independent mechanism. Cyclic AMP, which enhances ICa, and the cyclic nucleotide phosphodiesterase inhibitor, IBMX, both antagonize ICa depression induced by 8-Br-cGMP, but not that due to phorbol esters. Cyclic IMP, a more potent activator of phosphodiesterase than of cGMP-dependent protein kinase, is also a powerful depressant of ICa. We conclude that cGMP-induced depression of ICa is mediated by activation of cyclic nucleotide phosphodiesterase with consequent reduction of intracellular cAMP.
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PMID:Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. 285 1

Membrane-permeable cAMP analogs or elevation of intracellular cAMP by cyclic nucleotide phosphodiesterase (PDE) inhibitors activates cAMP-dependent protein kinase. Biologically active phorbol esters or diacylglycerol activate the calcium-, phospholipid-dependent protein kinase, protein kinase C (PK-C). We report that membrane-permeable cAMP analogs, PDE inhibitors, biologically active phorbol esters, or a synthetic diacylglycerol inhibited cleavage of 1-cell mouse embryos to the 2-cell stage. The cAMP analogs and PDE inhibitors were effective only when added prior to S of the first cell cycle, whereas PK-C activators inhibited cleavage when added up until late G2/M. The PDE inhibitor Ro 20 1724/1 inhibited both DNA and protein synthesis in 1-cell embryos, whereas the phorbol ester, 12-O-tetradecanoyl-phorbol-13 acetate, or alpha-amanitin did not. In addition, 1-cell embryos prevented from cleaving by PDE inhibitors did not show specific changes in the pattern of protein phosphorylation associated with the 2-cell embryo, whereas such changes occurred in 1-cell embryos inhibited from cleaving with PK-C activators. Transcription in the 2-cell embryo results in the synthesis of a specific set of proteins, which is inhibited by alpha-amanitin. Although treatment of 1-cell embryos with aphidicolin or PK-C activators during G1 did not inhibit the synthesis of these proteins, treatment with cAMP analogs or PDE inhibitors during G1 inhibited the appearance of these proteins. These results are discussed in terms of how the synthesis of transcription-dependent proteins in the 2-cell embryo may be regulated by protein phosphorylation.
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PMID:Differential effects of activators of cAMP-dependent protein kinase and protein kinase C on cleavage of one-cell mouse embryos and protein synthesis and phosphorylation in one- and two-cell embryos. 303 3


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