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)

Treatment of isolated rat adipocytes with tumor-promoting phorbol esters, caused a fivefold stimulation of glucose oxidation, determined as 14CO2 production from [1-14C]glucose and a fivefold increase in the rate of lipid synthesis from [14C]glucose. Treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate increased the rate of 86Rb+ uptake into the cells. Also phospholipase C was able to stimulate the rate of glucose oxidation; phospholipase C and 12-O-tetradecanoylphorbol 13-acetate stimulated glucose oxidation in a non-synergistic fashion, indicating a common mechanism for their action. Active phorbol esters and, in part, also phospholipase C, caused a translocation of protein kinase C activity from the soluble to the particulate fraction of the adipocytes. This process was rapid, being complete 30 s after the addition of phorbol ester, and resulted in the appearance of the kinase mainly in the mitochondrial and plasma membrane fractions. A comparison between the binding characteristics of adipocyte protein kinase C and the metabolic effects of the phorbol esters on the adipocytes revealed that the dose-response relationship did not correlate with binding of the phorbol esters, but, rather, a correlation was observed between the dose of phorbol esters required for translocation of protein kinase C and the intracellular effects. The results indicate that the intracellular translocation of protein kinase C might be a trigger for the effects of phorbol esters on the adipocyte and that binding of the esters to protein kinase C is not a sufficient event to cause this effect. Furthermore, it is suggested that activation of protein kinase C might be partly the action of hormones, such as insulin, on the fat cells.
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PMID:Rapid effects of phorbol esters on isolated rat adipocytes. Relationship to the action of protein kinase C. 315 18

1-0-Alkyl-2-0-methyl-sn-glycero-3-phosphocholine (alkylmethoxy-GPC) exerts a highly selective cytotoxic activity towards a variety of tumor cells that is not seen in normal cells. Human promyelocytic leukemia (HL-60) cells are particularly sensitive to this cytotoxic action. In this report we show that when HL-60 cells are differentiated into a granulocytic form by dimethylsulfoxide (Me2SO)they become resistant toward the cytotoxic effects of alkylmethoxy-GPC. Also, after short-term exposures of the HL-60 cells to alkylmethoxy-GPC, the uptake of [methyl-3H]choline is inhibited in the undifferentiated cells, but not in those differentiated with Me2SO. Thus, cellular choline uptake appears to be a useful index for assessing the susceptibility of cells to the cytotoxic effects of antitumor phospholipids. [3H]Alkylmethoxy-GPC is poorly metabolized by both cell populations as is evident by the trace quantities of labeled metabolites formed; also, alkylmethoxyglycerols do not exert any cytotoxic activity toward undifferentiated cells. These results demonstrate that differences in the cytotoxic response of sensitive (undifferentiated) and resistant (differentiated) cells to alkylmethoxy-GPC are not due to differences in their ability to metabolize alkylmethoxy-GPC or to a phospholipase C-generated toxic metabolite. Instead the data support our earlier hypothesis that the antitumor action of alkylmethoxy-GPC is, at least in part, caused by an impaired transport of small molecules across the membrane of sensitive cells.
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PMID:HL-60 cells become resistant towards antitumor ether-linked phospholipids following differentiation into a granulocytic form. 317 23

Several responses suggested to be critical components of phorbol ester tumor promotion were compared in 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion-sensitive SSIN and TPA promotion-resistant C57BL/6J mice. SSIN mice treated topically with 2 micrograms of TPA showed extensive hyperplasia accompanied by edema, measured as a 26% increase in water content of the skin. Only a very slight hyperplasia and 7% increased water content occurred after TPA treatment of C57BL/6J mice. The induction of ornithine decarboxylase was determined to be the same both in vivo and in vitro for SSIN and C57BL/6J mice, which does not correlate with the histological observations. Because hyperplasia and inflammation can be mediated by arachidonic acid metabolites, it was hypothesized that differences in this metabolic pathway would correlate with the histological responses. No significant qualitative or quantitative differences, however, were observed in the profiles of the major cyclooxygenase products between the strains of mice. Prostaglandin E2, the principal prostaglandin, was synthesized at a 3-fold greater level than prostaglandins D2 or F2 alpha in response to TPA. The most abundant lipoxygenase product was 12-hydroxyeicosatetraenoic acid followed by 8-, 15-, and 5-hydroxyeicosatetraenoic acid. 8-Lipoxygenase activity is elevated 24 h after TPA treatment in the SSIN mice by approximately 4-fold; no elevation is seen in C57BL/6J mice. A comparison of the oxidant response to TPA as well as to phospholipase C showed that SSIN epidermal cells generated a higher level, measured by chemiluminescence, than C57BL/6J cells. This suggests that oxidant generation or possibly 8-lipoxygenase activity may be the basis for the sensitivity or resistance to TPA as a hyperplasiogen and as a tumor promoter.
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PMID:Phorbol ester induction of 8-lipoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation but not ornithine decarboxylase induction. 333 28

Mitogenic stimulation of quiescent human fibroblasts (HSWP) with serum or a mixture of growth factors (consisting of vasopressin, bradykinin, EGF, and insulin) stimulates the release of inositol phosphates, mobilization of intracellular Ca, activation of Na/H exchange and subsequent incorporation of [3H]-thymidine. We have determined previously that pretreatment with the tumor-promoting phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate (TPA) inhibits mitogen-stimulated Na influx in HSWP cells. We report herein that TPA pretreatment also substantially inhibits the mitogen-stimulated release of inositol phosphates in HSWP cells. Half maximal inhibition of mitogen-stimulated inositol phosphate release occurs at 1-2 nM TPA. Treatment of cells with TPA alone has no effect on inositol phosphate release. The effect of TPA pretreatment on inositol phosphate release induced by individual growth factors has also been determined. Orthovanadate, reported by Cassel et al. (1984) to increase Na/H exchange in A431 cells, has been demonstrated to stimulate both Na influx and inositol phosphate release in HSWP cells. TPA pretreatment also inhibits both orthovanadate-stimulated inositol phosphate release and Na influx. In addition, orthovanadate was determined to increase intracellular Ca activity by mobilizing intracellular calcium stores, as determined with the fluorescent intracellular calcium probe fura-2. TPA pretreatment blocks orthovanadate stimulated mobilization of intracellular Ca stores. It appears clear that in HSWP cells pretreatment of cells with phorbol ester is capable of artificially desensitizing the early cellular responses to mitogenic stimuli (growth factors, orthovanadate) by blocking the signal transduction mechanism involved at a point prior to the release of inositol phosphates. We hypothesize that in HSWP cells the normal desensitization of both inositol phosphate release and Na/H exchange is mediated via activation of protein kinase C subsequent to the stimulus-mediated activation of phospholipase C and release of protein kinase C activator diacylglycerol. However it is interesting to note that TPA-mediated inhibition of these early responses in HSWP cells does not inhibit their ability to be stimulated to incorporate [3H]-thymidine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of phorbol ester on mitogen and orthovanadate stimulated responses of cultured human fibroblasts. 334 37

Synthetic alkyl lysophospholipids (ALP) show antineoplastic activity. In the present discussion, the cytotoxicity of ALP is attributed to their accumulation in tumor cells. Some neoplastic cell species, in contrast to normal cells, cannot metabolize ALP because of a lack of O-alkylglycerol monooxygenase (AGMO) activity. To understand the metabolic fate of ether lipids and ether-linked phospholipids, AGMO substrate specificity studies were undertaken. Thirty-five different natural and synthetic ether lipids and their metabolites (including a thioether) were tested as substrates for AGMO. The study revealed that the potent cytostatic substance, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine is not a substrate for AGMO. Therefore, its selective toxicity to tumor cells cannot be based on the differences in direct detoxification of 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine by AGMO in normal and malignant cells. However, 1-O-octadecyl-2-O-methyl-rac-glycerol, which can be formed by phospholipase C hydrolysis, is a good substrate for AGMO.
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PMID:Substrate specificity of O-alkylglycerol monooxygenase (E.C. 1.14.16.5), solubilized from rat liver microsomes. 344 74

Recent studies have shown that the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulates protein kinase C (PKC), whereas the ether-linked phospholipid 1-O-octadecyl-2-O-methyl-rac-glycerol-3-phosphocholine (ET-18-OCH3) inhibits PKC activity in vitro. Therefore, the antitumor effects of ET-18-OCH3 could be due to its inhibition of PKC activity and the effects of tumor promotion. TPA stimulates arachidonic acid release, prostaglandin synthesis, phosphatidylcholine synthesis and the degradation of phosphatidylcholine by phospholipase C in Madin Darby canine kidney (MDCK) cells. Therefore, we have determined the effects of ET-18-OCH3 on these consequences of TPA stimulation. Preliminary experiments determined that ET-18-OCH3 inhibited PKC partially purified from MDCK cells by ion-exchange chromatography on DEAE-cellulose. In addition, ET-18-OCH3 inhibited the TPA-stimulated phosphorylation of a 40,000-dalton protein in intact MDCK cells. These data indicate that ET-18-OCH3 is an effective inhibitor of PKC activity in MDCK cells. In addition, ET-18-OCH3 was found to inhibit arachidonic acid release and prostaglandin synthesis. The inhibition of prostaglandin synthesis appears to be secondary to inhibition of arachidonic acid release, since ET-18-OCH3 does not inhibit TPA-stimulated synthesis of prostaglandin H synthase or the activity of the enzyme directly (Parker, J., Daniel, L. W., and Waite, M. [1987] J. Biol. Chem. 262, 5385-5393). ET-18-OCH3 also inhibits TPA-stimulated phosphatidylcholine synthesis and phosphatidylcholine degradation by phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ether lipids inhibit the effects of phorbol diester tumor promoters. 344 77

The classic pathway for agonist-induced generation of diacylglycerol is via activation of a phospholipase C-mediated hydrolysis of the "phosphoinositides." We now report findings from a variety of cell types, which indicate that tumor-promoting phorbol diesters, serum, and platelet-derived growth factor activate within seconds the hydrolysis of phosphatidylcholine, as detected by the formation of diacylglycerol and phosphocholine. It is known that phorbol diesters do not stimulate hydrolysis of the phosphoinositides. Yet, in cells prelabeled with either [14C]oleate or [32P]orthophosphate, addition of the tumor promoter phorbol dibutyrate (PBt2) resulted in the rapid generation of both diacylglycerol and phosphatidate in a time- and dose-dependent manner. The fatty acid composition of the phosphatidate most resembled the fatty acid profile of phosphatidylcholine from the same cell type. Taken together, these findings suggested a role for protein kinase C in the generation of diacylglycerol (and phosphatidate) from phosphatidylcholine. To define further the pathways involved, the metabolism of cellular phosphatidylcholine was studied. In cells prelabeled with [3H]choline, addition of PBt2, but not 4 alpha-phorbol, stimulated the formation of intracellular phosphocholine within 45 sec. Furthermore, addition of platelet-derived growth factor (PDGF) or serum to "serum-starved" cells prelabeled with [3H]choline resulted in increased levels of intracellular phosphocholine within 15-30 sec. Thus, the data suggest that agonists that stimulate protein kinase C either directly (e.g., PBt2) or indirectly via activation of phosphoinositide hydrolysis (e.g., PDGF and serum) may stimulate degradation of phosphatidylcholine by phospholipase C in intact cells. However, prior down-regulation of protein kinase C by prolonged pretreatment of cells with PBt2 almost totally abolished subsequent stimulation of phosphatidylcholine degradation by PBt2 but only partially attenuated subsequent stimulation by PDGF and serum. These observations suggest that PDGF and serum act, at least partially, through a protein kinase C-independent mechanism. Lastly, the size of the cellular choline and CDP-choline pools were shown to be small and relatively insensitive to agonist addition, as compared to the size and behavior of the phosphocholine pool. Thus, the rapidly increased levels of phosphocholine (and diacylglycerol) arising in response to agonist addition appear to be derived directly from phosphatidylcholine by a phospholipase C-mediated mechanism.
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PMID:Rapid formation of diacylglycerol from phosphatidylcholine: a pathway for generation of a second messenger. 346 27

I examined whether the phorbol ester-mediated inhibition of glycerol 3-phosphate dehydrogenase (GPDH) induction could be mimicked by raising the cellular diacylglycerol levels. Phorbol ester tumor promoters and diacylglycerols activate protein kinase C. An increase in radiolabeled diacylglycerol levels in C6 rat glioma cells was observed when cells were prelabeled overnight with [3H]arachidonic acid and treated with either phospholipase C (Clostridium perfringens) or 2-bromooctanoate. The increase was dose dependent. The diacylglycerols competed with [20-3H]phorbol 12,13-dibutyrate in binding to the phorbol ester receptor. A Scatchard analysis of the binding of cells treated with 0.1 unit/ml of phospholipase C demonstrated that the inhibition was mainly due to a decrease in binding affinity and not in the total number of binding sites. 2-Bromooctanoate and phospholipase C, but not the synthetic diacylglycerol 1-oleoyl 2-acetyl glycerol, inhibited the glucocorticoid induction of GPDH levels. Boiled phospholipase C, phospholipase A2, or phospholipase D was ineffective in inhibiting induction, a result suggesting that the inhibition was not due to nonspecific membrane perturbation. Thus, inhibition of the glucocorticoid-mediated increase in GPDH induction is most likely mediated by protein kinase C, and not by an alternate phorbol ester receptor.
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PMID:Increased diacylglycerol levels inhibit [20-3H]phorbol 12,13-dibutyrate binding and the glucocorticoid-mediated increase in glycerol phosphate phosphate dehydrogenase levels in C6 rat glioma cells. 346 28

Staphylococcus aureus alpha-toxin, at sub-cytotoxic concentrations, inhibits both the 125I-labeled epidermal growth factor (EGF) binding and autophosphorylation properties of EGF-receptors in PC12 cells. This inhibition occurred only in intact cells and is probably due to a decrease in the affinity of the receptor for EGF. Streptolysin S and parcelsin could mimic the alpha-toxin effect below cytotoxic concentrations, as measured by a 51Cr release assay. In contrast, other membrane perturbing toxins with different lipid specificity, such as tetanolysin and cobra direct lytic factor, inhibited [125I]EGF binding only at cytotoxic concentrations. Staphylococcal alpha-toxin also stimulated 3-fold the specific binding of a radioactive tumor-promoting phorbol ester (PDBu) to PC12 cells at concentrations similar to those required for the inhibition of [125I]EGF binding. Although the exact mechanism for the inhibition of EGF binding by alpha-toxin has not been established, our results suggest that protein kinase C may be involved in this time-dependent process.
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PMID:Staphylococcus aureus alpha-toxin. 2. Reduction of epidermal growth factor receptor affinity in PC12 cells. 349 39

Bombesin caused a marked stimulation of 32Pi into phosphatidylinositol (PI), with no apparent lag, and into phosphatidylcholine (PC), after a lag of about 20 min. Stimulation was blocked by the bombesin receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11] substance P, indicating that the effects on both PI and PC were mediated through the same receptor. The tumor-promoting phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) and dioctanoylglycerol (diC8) both directly activate protein kinase C and in this report were shown to stimulate 32Pi incorporation into PC but not into Pl. In addition, TPA stimulated the release of [3H]choline and [3H]phosphocholine and the accumulation of [3H]diacyglycerol from prelabelled cells. These results strongly suggest that TPA activates a phospholipase C specific for PC. Pretreatment of cells with phorbol-12, 13-dibutyrate (PDBu) for 24 h depleted cellular protein kinase C activity and inhibited the ability of TPA to induce these effects suggesting a direct involvement of protein kinase C. Similarly the bombesin stimulation of 32Pi into PC and of [3H]choline and [3H]phosphocholine release was inhibited by PDBu pretreatment. DiC8 and, to a lesser extent, TPA stimulated the translocation of CTP:phosphocholine cytidylytransferase from the cytosolic to the particulate fraction. DiC8 also stimulated this translocation in cells depleted of protein kinase C. It was concluded that both bombesin and TPA activated protein kinase C leading to activation of a phospholipase C specific for PC.
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PMID:Bombesin and phorbol ester stimulate phosphatidylcholine hydrolysis by phospholipase C: evidence for a role of protein kinase C. 355 93


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