Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown that modulation of intracellular calcium in EBV latently infected cells could induce the expression of viral antigens, and suggested that a protein kinase-C (PKC) may play a major role in the EBV genome activation. We now report further investigations on the role of PKC using 2 selective enzymatic inhibitors [1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine] (H-7) and Staurosporine. We show that these inhibitors can abrogate the inductive effect of TPA or the combination of TPA plus n-butyrate. The inhibitors have no effect on induction by calcium ionophores or by viral superinfection. In this context the effect of verapamil (a specific calcium channel blocker) and of several calmodulin antagonists was investigated. No inhibitory effect of these agents could be demonstrated on any of the induction systems examined. These observations strengthen the idea that in some instances cellular PKC plays a role in the expression of viral antigens; however, alternative regulatory mechanisms cannot be excluded.
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PMID:TPA induction of Epstein-Barr virus early antigens in Raji cells is blocked by selective protein kinase-C inhibitors. 282 40

Staurosporine, microbial alkaloid which has been known to have antifungal activity was found to inhibit markedly phospholipid/Ca++dependent protein kinase (protein kinase C) from rat brain, with an IC50 value of 2.7 nM. However, it had little effect on the binding of 3H-phorbol-12, 13-dibutyrate (PDBu) to protein kinase C. The inhibition of protein kinase C was not competitive with phospholipid. This compound also showed the strong cytotoxic effect on the growth of HeLa S3 cells, with an IC50 value of 4 X 10(-12)M under the condition of 72 hr-exposure.
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PMID:Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. 345 62

Adjacent, parentally imprinted, insulin-like growth factor-II (IGF-II) and H19 genes are highly expressed during embryogenesis and are important for fetal growth. Human fetal adrenals express abundantly both IGF-II and H19 genes. To clarify the significance and regulation of the H19 gene, we studied its expression in fetal adrenals. In situ hybridization experiments showed H19 RNA expression throughout the fetal adrenal cortex, with slightly higher expression in the outer definitive (adult) than in the inner fetal zone. In primary cultures of fetal adrenal cells, ACTH and other activators of the protein kinase-A signal transduction pathway increased both H19 and IGF-II RNA accumulation 1.7- to 10-fold. Staurosporine, a protein kinase-C inhibitor, increased H19 and IGF-II RNA to the same extent as did ACTH. The protein kinase-C activator 12-O-tetradecanoyl phorbol-13-acetate and cytokines, tumor necrosis factor-alpha and interferon-gamma, inhibited H19 and IGF-II RNA accumulation. Transforming growth factor-beta 1 caused a decrease in levels of H19 and IGF-II RNA, whereas the IGFs caused a slight increase. Our data show parallel multifactorial regulation of H19 and IGF-II RNAs in human fetal adrenal cells. This suggests common regulatory mechanisms for these adjacent genes.
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PMID:Parallel regulation of parentally imprinted H19 and insulin-like growth factor-II genes in cultured human fetal adrenal cells. 751 97

Previous studies have demonstrated that the alpha v beta 5 integrin receptor functions in the endocytosis and degradation of matrix-bound vitronectin by human skin fibroblasts (Panetti, T. S., and McKeown-Longo, P. J. (1993) J. Biol. Chem. 268, 11988-11993; Panetti, T. S., and McKeown-Longo, P. J. (1993) J. Biol. Chem. 268, 11492-11495). These earlier studies demonstrated that vitronectin degradation was inhibited by either antibodies to the beta 5 integrin or exogenous heparin, suggesting that both integrin receptors and cell surface heparan sulfate proteoglycans are involved in the endocytosis and degradation of vitronectin. The present study was done to define intracellular signaling pathways involved in endocytosis of vitronectin and to evaluate the relative contribution of cell surface heparan sulfate proteoglycans and the alpha v beta 5 integrin in the activation of these signaling pathways. The addition of the phorbol ester phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, to monolayers of human skin fibroblasts, increased vitronectin degradation. Staurosporine and calphostin C, inhibitors of protein kinase C, blocked internalization and subsequent degradation of vitronectin, while KT5720, an inhibitor of protein kinase A, had no effect on the degradation of vitronectin. PMA was also able to reverse the inhibition of vitronectin degradation seen when cells were pretreated with heparinase or incubated with exogenous heparin. In contrast, the inhibitory effect of either RGD peptides or anti-alpha v beta 5 antibodies on vitronectin degradation were not overcome by the addition of PMA. These data suggest that the internalization of vitronectin from the matrix is mediated by the alpha v beta 5 integrin following activation of protein kinase C.
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PMID:Alpha v beta 5 integrin receptor-mediated endocytosis of vitronectin is protein kinase C-dependent. 754 5

The effect of protein kinase C activators and inhibitors on histamine-stimulated phospholipase C in bovine adrenal medullary cells has been investigated. The protein kinase C activators, phorbol 12,13-dibutyrate (PDB) or sn-1,2-dioctanoylglycerol (DOG), inhibited histamine-stimulation of phospholipase C. This inhibition was prevented by the protein kinase C-selective inhibitor Ro 31-8220 (3-[1-[3-(2-isothioureido) propyl]indol-3-yl]-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dio ne) but not the broad spectrum protein kinase inhibitor staurosporine. Indeed staurosporine on its own inhibited both the histamine-stimulated response and, in permeabilized cells, phospholipase C activated by Ca2+. Staurosporine inhibition of phospholipase C is unlikely to be mediated via protein kinase A or Ca2+/calmodulin-dependent protein kinase because it was not reproduced by selective inhibition of these kinases. Staurosporine treatment, however, reduced inositol phospholipid levels in stimulated cells. Thus staurosporine and Ro 31-8220, two widely used protein kinase C inhibitors, have quite different effects on phospholipase C activation. Furthermore, staurosporine may cause this inhibition through a reduction in the level of phospholipase C substrate.
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PMID:Staurosporine inhibits inositol phosphate formation in bovine adrenal medullary cells. 758 17

Elevated levels of tissue inhibitor of metalloproteases-1 (TIMP-1) have been demonstrated in inflamed synovial membranes, and it is believed that the inhibitor may play a critical role in the regulation of connective tissue degradation. The present study was undertaken to define the cellular mechanism of action of the inflammatory mediators, interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2), in the control of TIMP-1 synthesis and expression in human synovial fibroblasts. Recombinant human IL-1 beta induced a time- and dose-dependent saturable response in terms of TIMP-1 mRNA expression (effective concentration for 50% maximal response, EC50 = 31.5 +/- 3.3 pg/ml) and protein synthesis (EC50 = 30 +/- 3.3 pg/ml). The protein kinase C (PKC) inhibitors, H-7, staurosporine, and calphostin C, reversed the rhIL-1 beta induction of TIMP-1 mRNA. PGE2 also inhibited rhIL-1 beta-stimulated TIMP-1 mRNA expression and protein secretion in a dose-dependent fashion. The concentration of PGE2 necessary to block 50% of rhIL-1 beta-stimulated TIMP-1 secretion, IC50, was 1.93 ng/ml (4.89 nM). Forskolin, and other stable derivatives of cAMP, mimicked, to a large extent, the effects of PGE2. The phorbol ester, PMA, up-regulated considerably the mRNA expression of TIMP-1 but had no effect on protein production. Calphostin C substantially reduced PMA-activated TIMP-1 expression. Staurosporine, calphostin C, H-7, and substances that elevate cellular levels of cAMP, like PGE2, also reduced basal expression and synthesis of TIMP-1. Taken together, the data suggest that PKA and C may mediate opposing effects in terms of TIMP-1 expression and secretion in human synovial fibroblasts.
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PMID:Interleukin-1 beta induction of tissue inhibitor of metalloproteinase (TIMP-1) is functionally antagonized by prostaglandin E2 in human synovial fibroblasts. 761 46

Enteroaggregative Escherichia coli (EAggEc) strains are associated with persistent diarrhea in children in the developing world and exhibit a classic aggregative phenotype. We have demonstrated that EAggEc strains isolated from children with persistent diarrhea in Brazil, Bangladesh, and Pakistan also have the potential to be internalized by HeLa cells in the gentamicin protection assay. We have confirmed this phenomenon with transmission electron micrographs of bacteria engulfed by HeLa cells. We examined the mechanisms by which this process occurs. Staurosporine inhibited internalization of EAggEc strain 162 by 50% at a concentration of 0.1 microM. Genistein inhibited internalization of this same organism by 50% at a concentration of 50 microM. Cytochalasin D inhibited internalization by 50% at a concentration of 1 microgram/ml. Staurosporine, genistein, and cytochalasin D inhibited the internalization of EAggEc strain 162 by HeLa cells in a dose-dependent manner. These data suggest that active cell processes such as signal transduction by protein kinase and/or tyrosine kinase may be involved in the internalization of EAggEc strain 162 by HeLa cells and that actin filaments and cytoskeletal structure may be important for this process.
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PMID:Characterization of an invasive phenotype associated with enteroaggregative Escherichia coli. 764 71

Whole-cell patch-clamp recordings and single-cell Ca2+ measurements were used to study the control of Ca2+ entry through the Ca2+ release-activated Ca2+ influx pathway (ICRAC) in rat basophilic leukemia cells. When intracellular inositol 1,4,5-trisphosphate (InsP3)-sensitive stores were depleted by dialyzing cells with high concentrations of InsP3, ICRAC inactivated only slightly in the absence of ATP. Inclusion of ATP accelerated inactivation 2-fold. The inactivation was increased further by the ATP analogue adenosine 5'-[gamma-thio]triphosphate, which is readily used by protein kinases, but not by 5'-adenylyl imidodiphosphate, another ATP analogue that is not used by kinases. Neither cyclic nucleotides nor inhibition of calmodulin or tyrosine kinase prevented the inactivation. Staurosporine and bisindolylmaleimide, protein kinase C inhibitors, reduced inactivation of ICRAC, whereas phorbol ester accelerated inactivation of the current. These results demonstrate that a protein kinase-mediated phosphorylation, probably through protein kinase C, inactivates ICRAC. Activation of the adenosine receptor (A3 type) in RBL cells did not evoke much Ca2+ influx or systematic activation of ICRAC. After protein kinase C was blocked, however, large ICRAC was observed in all cells and this was accompanied by large Ca2+ influx. The ability of a receptor to evoke Ca2+ entry is determined, at least in part, by protein kinase C. Antigen stimulation, which triggers secretion through a process that requires Ca2+ influx, activated ICRAC. The regulation of ICRAC by protein kinase will therefore have important consequences on cell functioning.
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PMID:Depletion-activated calcium current is inhibited by protein kinase in RBL-2H3 cells. 764 12

Addition of 100 nM phorbol 12-myristate 13-acetate (PMA), an active phorbol diester, to quiescent cultured Madin-Darby canine kidney (MDCK) cells caused a maximal stimulation of phosphatidylethanol formation within 1-2 h in the presence of 1% ethanol, indicating the activation of phospholipase D (PLD). The specificity of phorbol diesters for the activation of PLD activation was confirmed by the fact that phorbol 12,13-dibutyrate (PDBu) was effective, whereas 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD) was without effect. Down-regulation caused by the long-term pretreatment of the cells with active phorbol diesters significantly decreased the production of phosphatidylethanol. Staurosporine, a well known protein kinase (PK)C inhibitor at 1 microM, decreased the activation of PLD. Taken together, these observations suggested the involvement of PKC in the activation of PLD. The cellular PLD activity was found to be selectively localized in the particulate fraction by centrifugation at 12,000 x g. The particulate PLD showed the selective substrate specificity for phosphatidylcholine rather than phosphatidylethanolamine. In response to the addition of 100 nM PMA, 1,2-diacylglycerol (DG) increased in a biphasic fashion. In view of the time course of the activation of PLD, the second increase in the 1,2-DG around 20 min was contributed by the activation of PLD. In response to the simultaneous addition of 100 nM PMA and 100 nM A23187, the cultured MDCK cells activated the arachidonate cascades to form prostaglandin (PG)E2 and PGF2 alpha as major products, requiring slower 24 h to reach maximal levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation mechanism of phospholipase D involved in the generation of lipid mediators in cultured Madin-Darby canine kidney cells. 767 Jan 90

Treatment with 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) (1-12 h, 10(-10) M) stimulates DNA synthesis in proliferating myoblasts, with an early response at 2-4 h of treatment followed by a maximal effect at 10 h. To investigate the mechanism involved in the mitogenic action of the hormone we studied the possible activation of intracellular messengers by 1,25(OH)2D3. The initial phase of stimulation of [3H]thymidine incorporation into DNA by the sterol was mimicked by the protein kinase C activator tetradecanoylphorbol acetate (TPA) in a manner which was dose dependent and specific as the inactive analog 4 alpha-phorbol was without effect. Maximal responses to TPA (100 nM) were obtained at 4 h. Staurosporine, a protein kinase C inhibitor, blocked the effect of 1,25(OH)2D3 on myoblast proliferation at 4 h. In addition, a fast (1-5 min) elevation of diacylglycerol levels and membrane-associated protein kinase C activity was observed in response to 1,25(OH)2D3. The adenylate cyclase activator forskolin (20 microM) and dibutyryl-cAMP (50 microM) increased DNA synthesis reproducing the second 1,25(OH)2D3-dependent stimulatory phase at 10 h. Inhibitors of protein kinase A blocked the increase in muscle cell DNA synthesis induced by 1,25(OH)2D3 at 10 h. Significant increases in cyclic AMP levels were detected in myoblasts treated with the sterol for 1-10 h. The calcium channel antagonist nifedipine (5-10 microM) abolished both the effects of 4-h treatment with 1,25(OH)2D3 or TPA and 10-h treatment with 1,25(OH)2D3 or dibutyryl-cAMP. Similar to the calcium channel agonist Bay K8644, 1,25(OH)2D3 stimulated myoblast 45Ca uptake and its effects were blocked by nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for the participation of protein kinase C and 3',5'-cyclic AMP-dependent protein kinase in the stimulation of muscle cell proliferation by 1,25-dihydroxy-vitamin D3. 768 42


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