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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biologically active 125I-cytotoxin from Pseudomonas aeruginosa binds to plasma membranes from Ehrlich ascites tumor cells in a saturable manner. The Scatchard plot indicated a single binding site with a capacity of 260 pmoles/mg of membrane protein and a KD of 2 X 10(-8) M. Specific binding was dependent on temperature, pH and ionic strength. Thus constant levels of bound 125I-cytotoxin were attained either within 30 min at 30 degrees C or within 3 h at 4 degrees C. Binding was 30-fold higher at 4 degrees C vs 30 degrees C and 2-6-fold higher at pH 5.3 vs pH 8.3. Binding was not effected by 50 mM sugar or sialic acid. 300 mM sucrose, however, instead of phosphate buffer, reduced binding by 50%. Pretreatment of plasma membranes with trypsin or papain led to a significant decrease in 125I-cytotoxin binding. A pretreatment with phospholipase C or D had no effect, whereas phospholipase A2 induced a decrease by 34%. The collected data suggest that the binding site for 125I-cytotoxin within the plasma membrane from Ehrlich ascites tumor cells is a membrane protein. Correlation of 125I-cytotoxin binding and membrane action of the unlabelled cytotoxin can be observed through (a) increased lowering of the cellular K+ and Na+ gradient by decrease of medium pH, (b) decreased toxicity after substitution of ions by sugar, and (c) increased breakdown of cellular cationic gradient after temperature shift from 4 degrees C to 37 degrees C.
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PMID:Interaction of Pseudomonas aeruginosa cytotoxin with plasma membranes from Ehrlich ascites tumor cells. 300 83

Leukotriene B4 (LTB4) induced rapid breakdown of prelabeled inositol phospholipids in rat peritoneal polymorphonuclear leukocytes (PMNs). Formation of [3H]inositol triphosphate ([3H]IP3) was rapid, with a peak of 250-300% of the control level, after 5-15 sec of exposure to LTB4. Accumulation of [3H]inositol bisphosphate was rapid, peaking after 30 sec of treatment. Accumulation of [3H]inositol monophosphate was also rapid in the presence of LiCl. The kinetics of [3H]IP3, [3H]inositol bisphosphate, and [3H]inositol monophosphate accumulation suggest that LTB4 may interact with receptors in PMNs and activate phospholipase C which in turn induces hydrolysis of inositol-phospholipids. The agonist activities of several LTB4 analogs were employed to investigate the structure-activity relationships of LTB4 receptor-mediated activation of phosphatidylinositol hydrolysis. Increases in [3H]IP3 formation were dependent upon the concentration of LTB4 and the agonist analogs. The rank order potency of these analogs was equivalent to that of the pharmacological activity of LTB4 agonists in the PMN chemotaxis assay. Furthermore, the islet activation protein isolated from Bordetella pertussis inhibited LTB4-induced [3H]IP3 formation. The tumor-promoting phorbol myristate acetate also inhibited LTB4-induced [3H]IP3 formation. The LTB4 receptors on a partially purified PMN membrane were characterized. LTB4 binding to the receptors was stereoselective and specific. The binding affinity (Kd) of [3H] LTB4 to the receptors was 1.3 +/- 0.2 nM. The maximum density of binding was 5.5 +/- 1.8 pmol/mg of protein. The rank order potency of binding affinities of several LTB4 analogs was equivalent to that of the induction of IP3 response induced by LTB4 and analogs. These results suggest that LTB4 may interact with receptors in rat PMNs, activate G protein-regulated phospholipase C, and induce [3H]IP3 formation.
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PMID:Leukotriene B4 induces formation of inositol phosphates in rat peritoneal polymorphonuclear leukocytes. 301 80

Ouabain-sensitive 86Rb+ uptake by isolated rat hepatocytes was studied to elucidate how Ca2+-mobilizing hormones stimulate the Na+-pump. Stimulation of this uptake was observed with concentrations of vasopressin ([8-arginine]vasopressin, AVP), angiotensin II, and norepinephrine which elicited Ca2+ mobilization and phosphorylase activation. These results suggested that changes in cytosolic Ca2+, mediated by inositol trisphosphate, might trigger sodium pump stimulation by AVP. However, in hepatocytes incubated in Ca2+-free Krebs-Henseleit buffer, Na+-pump activity was not altered over 15 min by either 1.5 mM EGTA or 1.5 mM Ca2+. Furthermore, incubation of cells in 5 mM EGTA for 15-30 min drastically impaired the ability of AVP to increase cytosolic Ca2+, but only modestly attenuated AVP-stimulated Na+-pump activity. Two tumor promoters, phorbol myristate acetate (PMA) and mezerein, stimulated Na+/K+-ATPase-mediated transport activity. Similarly, addition of synthetic diacylglycerols or of exogenous phospholipase C from Clostridium perfringens to increase endogenous diacylglycerol levels also resulted in a stimulation of the Na+-pump in the absence of changes in cytosolic or total cellular Ca2+ levels. Stimulation of the Na+-pump by the combination of maximal concentrations of PMA and AVP did not produce an additive response, and both agents displayed a transient time course, suggesting that the two agents share a common mechanism. Stimulation of the Na+-pump by AVP and PMA was not blocked by amiloride analogs which inhibit Na+/H+ exchange, but these compounds blocked the action of insulin. These data suggest that the elevated Na+/K+-ATPase-mediated transport activity observed in hepatocytes following exposure to Ca2+-mobilizing hormones is a consequence of stimulated diacylglycerol formation and may involve protein kinase C.
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PMID:The hormone-sensitive hepatic Na+-pump. Evidence for regulation by diacylglycerol and tumor promoters. 302 43

Interactions among lithium, calcium, and phorbol esters in the regulation of adrenocorticotropin hormone (ACTH) release were examined in a tumor cell line (AtT-20) of the anterior pituitary. Lithium, which blocks the phosphatase that converts inositol phosphates (IPs) to inositol, increases the levels of IPs in these cells and stimulates ACTH release. This ion potentiates the ability of calcium, an activator of phospholipase C, to raise levels of IPs in these cells and to stimulate ACTH secretion. Pretreatment of AtT-20 cells with calcium specifically abolishes the ACTH release response to lithium or calcium, a result suggesting that these secretagogues may act through a common mechanism to induce hormone secretion. Prior exposure of AtT-20 cells to either lithium or calcium also attenuates the ACTH release induced by phorbol ester, an activator of protein kinase C. To examine the link among lithium, calcium, phosphatidylinositol (PI) turnover, and phorbol ester-evoked ACTH secretion, AtT-20 cells were treated with 1-oleoyl-2-acetoyl-sn-3-glycerol (OAG), an analogue of the diacylgylcerols that are formed by phospholipase C during PI metabolism and that also activate protein kinase C. OAG itself does not alter ACTH release or the levels of IPs in AtT-20 cells. Pretreatment of AtT-20 cells with OAG, however, selectively blocks the ACTH release response to lithium, calcium, or phorbol ester. Furthermore, such pretreatment reduced the ability of lithium to increase levels of IPs. The results suggest that one mechanism of action of lithium is to potentiate selectively an action of calcium, possibly the stimulation of phospholipase C activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions among lithium, calcium, diacylglycerides, and phorbol esters in the regulation of adrenocorticotropin hormone release from AtT-20 cells. 303 56

The studies described above have led to some conclusions as well as some speculations regarding the participation of oncogenes in proliferation. It is important to make a clear distinction between the data described along with the resulting conclusions, and the highly speculative models which have been proposed here to describe these results. On the basis of the results described, several conclusions appear to be indicated. First, it is clear that in normal cells of many types ras proteins are required for proliferation. Second, these proteins are needed for the maintenance of the transformed phenotype induced by some, but not all, oncogenes. Third, the activity of ras proteins is not apparently involved in controlling the activity of phospholipase C or any other identifiable phospholipase. Finally, tumor formation appears to involve the development of a proliferative phenotype which functions independently of ras activity. To explain these data, a model of proliferative control is presented. This model is highly speculative at this time and is based upon the assumption that the "ras pathway" involves the sequential action of cellular genes related to the retroviral oncogenes. The function of this pathway is to pass the proliferative signal generated by an occupied growth factor receptor into the cell. It is clearly needed late in the G-1 phase of the cell cycle, but the "ras pathway" might also be involved in the early events associated with mitogenic stimulation. Due to its central role in the control of proliferation and the fact that tumor cells circumvent its action, ras proteins are postulated to a site of negative proliferative control. After the action of ras and related cellular oncogenes, the proliferative control signal no longer involves the action of a simple linear sequence of protein activities, but might involve multiple, interdependent pathways. This model is primarily of value as a working hypothesis and does not account for many observations central to proliferative control such as the involvement of cell-cell contact, differentiation, and the action of factors which inhibit rather than promote proliferation, such as interferons. The model does summarize the data described and even in the simplest form represents a novel approach to explain proliferative control in terms of the activities of known genes.
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PMID:The ras pathway: a model for the control of proliferation in animal cells. 306 84

The tumor promoter phorbol ester (PMA) has been shown to stimulate protein kinase C (PKC) in MDCK cells. At the concentrations that produce stimulation of PKC, PMA (100 microM) inhibits BK-induced I1,4,5P3 (IP3) formation and calcium transients in these cells. 1-5-isoquinolinyl-2-methyl-piperazine (H7) a known inhibitor of PKC in MDCK cells reverses the effect of PMA on BK-stimulated IP3 formation and Ca2+ transients in these cells. PMA also stimulates arachidonate release which can be inhibited by preincubation with H7. A dual mechanism of regulation by PKC at the level of phospholipase C (down regulation) and phospholipase A2 (stimulation) is suggested in these cells.
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PMID:Protein kinase C modulates phospholipase C and increases arachidonic acid release in bradykinin stimulated MDCK cells. 313 68

Platelet-derived growth factor (PDGF), the calcium ionophore A23187, and the tumor promoter phorbol myristate acetate stimulated c-fos mRNA levels in control NIH 3T3 cells. However, NIH 3T3 cells transformed by EJ-ras DNA transfection, which have diminished PDGF-stimulated phospholipase C activity, showed a 95% reduction in PDGF-stimulated c-fos mRNA levels. The responses to A23187 and phorbol myristate acetate were also attenuated, but not as severely as the PDGF-mediated induction. The reduction in PDGF-stimulated c-fos induction did not appear to be a general result of cellular transformation, since src-transformed NIH 3T3 cells displayed a strong PDGF-stimulated c-fos induction. Despite the reduction in PDGF-stimulated c-fos induction, EJ-ras-transformed cells still responded mitogenically to PDGF. These data suggest that the magnitude of c-fos induction cannot be directly correlated with PDGF-stimulated mitogenesis in EJ-ras-transformed NIH 3T3 cells.
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PMID:Platelet-derived growth factor does not induce c-fos in NIH 3T3 cells expressing the EJ-ras oncogene. 314 5

Calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), N-(6-aminohexyl)-1-naphthalenesulfonamide (W-5) and trifluoperazine inhibited ornithine decarboxylase induction in lymphocytes activated with phytohemagglutinin or inophore A23187. W-7, a more potent calmodulin antagonist than W-5, suppressed ornithine decarboxylase induction in a higher extent than did W-5. These results suggest that calmodulin may play an important role in ornithine decarboxylase induction in the activated lymphocytes. However, the extent of ornithine decarboxylase induction was greater in cells pretreated with Clostridium phospholipase C and then incubated with ionophore A23187 than in cells incubated with ionophore A23187 without the pretreatment. Moreover, combined treatment of cells with ionophore A23187 and tumor promotor, phorbol 12-myristate 13-acetate, caused synergistic induction of ornithine decarboxylase activity. These results, taken together, suggest that both activations of Ca2+-activated phospholipid-dependent protein kinase by diacylglycerol and of calmodulin-dependent function resulted from an elevation of cytosolic Ca2+ concentration may operate in the induction of ornithine decarboxylase in the activated lymphocytes.
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PMID:Induction of ornithine decarboxylase in guinea-pig lymphocytes. Synergistic effect of diacylglycerol and calcium. 315 35

Tumor-promoting phorbol esters induce ornithine decarboxylase (ODCase) activity and reduce epidermal growth factor (EGF) binding in rat tracheal epithelial 2C5 cells. Phorbol esters activate protein kinase C by interacting at the same site as sn-1,2-diacylglycerols, the presumed physiological regulators. The effects of added sn-1,2-diacylglycerols and those generated by phospholipase C treatment of 2C5 cells on ODCase induction and EGF binding were investigated to establish a role for protein kinase C in these cellular responses. Treatment of 2C5 cells with phospholipase C induced ODCase activity and reduced EGF binding, whereas phospholipases A2 and D were inactive. When sn-1,2-diacylglycerols containing fatty acids 3-10 carbons in length were added to 2C5 cells, those diacylglycerols containing fatty acids 5-10 carbons in length caused ODCase induction and reduction in EGF binding. sn-1,2-Dioctanoylglycerol was one of the most active compounds tested. It induced ODCase in a dose- (50-500 microM) and time-dependent manner. The reduction of binding of 125I-labeled EGF by sn-1,2-dioctanoylglycerol was also time and dose dependent and appeared to result from a change in EGF affinity and not the number of receptor sites. This series of sn-1,2-diacylglycerols showed similar structure-function relationships in their ability to induce ODCase activity, to decrease EGF binding, to stimulate protein kinase C, and to inhibit [3H]phorbol dibutyrate binding to the phorbol ester receptor. These data demonstrate biological activities for a number of diacylglycerols and indicate that protein kinase C activation is implicated in ODCase induction and decreased EGF binding.
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PMID:Role of protein kinase C in diacylglycerol-mediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding. 315 91

Using high-resolution 2-dimensional gel electrophoresis to separate proteins from cells labeled in vivo with either [32P]phosphate or [35S]methionine, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was shown to stimulate phosphorylation of at least 18 proteins in a subline of S49 mouse lymphoma cells deficient in cyclic AMP-dependent protein kinase. Phosphorylation of these proteins was not altered by phorbol acetate, a phorbol ester inactive in tumor promotion, and stimulation by TPA was half-maximal at less than 16 nM; therefore, these responses appeared to reflect specific interactions of TPA with high-affinity receptors. Treatment of cells with phospholipase C mimicked TPA in stimulating phosphorylation of some of these substrate proteins, thereby suggesting possible involvement of protein kinase C, the calcium-activated phospholipid-dependent protein kinase. Substrates differed in their relative responses to phospholipase C, the kinetics and concentration dependence of their phosphorylation in response to TPA, their extents of TPA-stimulated changes in phosphorylation, and their responses to tetracaine and retinal, two inhibitors of protein kinase C. Using these responses as criteria for classification, the TPA-mediated phosphorylations could be shown to fall into at least three distinct groups. The significance of these results to regulation of intracellular protein phosphorylation, to the relationship of protein kinase C and phorbol ester receptors, and to possible heterogeneity in kinases stimulable by phorbol ester tumor promoters is discussed.
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PMID:Phorbol ester-mediated protein phosphorylations in S49 mouse lymphoma cells. 315 48


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