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)

Phospholipase C-mediated release of inositol trisphosphate, followed by an increase in free intracellular calcium, is an important signal transduction pathway for several membrane receptors. In the present investigation, the coupling of various receptors to phospholipase C was studied in the human keratinocyte line HaCaT. Inositol trisphosphate formation was determined by anion-exchange chromatography, and the release of intracellular calcium was analysed with the fluorescence probe Fura-2 AM. Activation of HaCaT keratinocytes with bradykinin resulted in a time- and dose-dependent release of inositol trisphosphate and intracellular calcium, with an EC50 value of 50 nM for bradykinin-induced inositol trisphosphate formation. The mediators and cytokines IL-1, IL-4, IL-6, IL-8, EGF and TGF alpha, as well as bombesin, prolactin, carbachol, substance P and retinoic acid, did not activate this pathway. The inability of the mediators examined to activate phospholipase C may be due to lack of the respective cognate receptors or to the use of other signal transduction pathways.
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PMID:Inositol phosphate formation and release of intracellular free calcium by bradykinin in HaCaT keratinocytes. 830 79

Expression of phosphoinositide-specific phospholipase C (PLC)-gamma during the retinoic acid (RA)-induced differentiation of F9 teratocarcinoma stem cells was investigated. PLC-gamma activity and PLC-gamma protein content were decreased during the differentiation of F9 teratocarcinoma stem cells induced by a combination (RACT) of RA, dibutyryl cyclic AMP (C) and theophylline (T). However, PLC-gamma activity and protein levels in RA- or C- and T-treated F9 cells remained the same as that of the F9 stem cells. Northern analysis of the 5.4-kb PLC-gamma transcript in differentiated F9 cells by RACT revealed that RACT decreased the PLC-gamma gene expression. These results suggest that the expression of PLC-gamma is negatively controlled by RACT treatment in the differentiation of F9 teratocarcinoma stem cells.
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PMID:Reduced expression of PLC-gamma during the differentiation of mouse F9 teratocarcinoma cells. 838 2

The importance of cell-associated plasminogen activation in the extracellular matrix degradation processes is becoming increasingly evident. To elucidate the modulators of net plasminogen activation on the cell surface, we have recently established an assay system. Using this system, we examined the effects of several candidate modulators on cell surface plasminogen activator in the human fibrosarcoma cell line HT-1080 and the SV40-transformed human lung fibroblast cell line WI-38 VA 13 2RA. Although the majority of the candidates had no effect or a selective effect on either cell line, only retinoic acid markedly enhanced cell surface plasminogen activator activity in both HT-1080 and WI-38 VA13 2RA cells in a time-dependent manner. The effect of retinoic acid was neutralized by actinomycin D. The enhanced activity was inhibited by anti-uPA IgG and by pretreatment with phosphatidylinositol-specific phospholipase C. These findings suggest that retinoic acid increases the amount of receptor-bound uPA via de novo synthesis, and that it plays an important role in modulating cell-associated plasminogen activation.
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PMID:Retinoic acid enhances plasminogen activation on the cell surface. 857 37

The linkage between Gialpha2 and morphogen-induced promotion of F9 embryonic teratocarcinoma stem (F9 stem) cells to primitive endoderm was explored using probes of the mitogen-activated protein (MAP) kinase network. The morphogen-induced decline in Gialpha2 is shown to trigger activation of phospholipase C, thereby activating protein kinase C, MAP kinase, and cell progression to primitive endoderm. In the absence of retinoic acid, reduction-of-function mutants (Gialpha2-deficient) display the effects of morphogen, i.e. activation of phospholipase C, protein kinase C, MAP kinase, and progression to primitive endoderm. Gain-of-function mutants (expressing the Q205L activating-mutation of Gialpha2) displayed no activation of phospholipase C, protein kinase C, MAP kinase and no progression to primitive endoderm, even in the presence of retinoic acid. Selective inhibitors of protein kinase C, like the gain-of-function mutations, effectively block morphogen-induced progression to primitive endoderm. Morphogen triggers F9 stem cell progression by triggering Gialpha2 loss and thereby activation of downstream elements, including protein kinase C and MAP kinase.
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PMID:Morphogen-induced decline in Gialpha2 triggers F9 teratocarcinoma stem cell progression via phospholipase C and mitogen-activated protein kinase. 862 47

In human neutrophils, histamine H2-receptors mediate activation of adenylyl cyclase (AC) and inhibition of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced superoxide anion (O2-) formation, and in HL-60 promyelocytes, H2-receptors mediate parallel activation of AC, phospholipase C (PLC) and non-selective cation (NSC) channels. As all-trans-retinoic acid (RA) is successfully used in the differentiation therapy of acute promyelocytic leukaemia, we studied signal transduction in RA-differentiated HL-60 cells. Histamine and the H2-receptor agonist, impromidine, induced both rises in cAMP levels and cytosolic Ca2+ ([Ca2+]i). Substances acting at post-receptor sites to increase cAMP did not increase [Ca2+]i. H2- but not H1-receptor antagonists inhibited histamine-induced cAMP accumulation and rises in [Ca2+]i were more effectively inhibited by H2- than by H1-receptor antagonists. Histamine-induced rises in [Ca2+]i were completely dependent on the presence of extracellular Ca2+ and were abolished by the blocker of NSC channels, Gd3+, but were resistant to inhibition by pertussis toxin. Unlike FMLP, histamine did not activate PLC. The effects of FMLP on [Ca2+]i were less sensitive to blockade by Gd3+ than those of histamine, and there was no cross-desensitization between the two stimuli. FMLP, but not histamine, inhibited transiently thapsigargin-induced rises in [Ca2+]. Taken together, our results show that histamine activates AC-mediated cAMP accumulation in RA-differentiated HL-60 cells via H2-receptors and NSC channel-mediated Ca2+ influx via H2- (and H1)-receptors. Histamine-induced NSC channel activation is not the consequence of AC- or PLC stimulation and occurs, directly or indirectly, via pertussis toxin-insensitive guanine nucleotide-binding proteins. FMLP and histamine activate Ca2+ influx by different mechanisms. There are similarities in H2-receptor-mediated signal transduction between RA-differentiated HL-60 cells and HL-60 promyelocytes and differences between the former cells and neutrophils, indicating that RA-differentiated HL-60 cells must be considered as partially immature.
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PMID:Stimulation of histamine H2- (and H1)-receptors activates Ca2+ influx in all-trans-retinoic acid-differentiated HL-60 cells independently of phospholipase C or adenylyl cyclase. 871 51

Multiple cellular responses are regulated through the generation of lipid second messengers upon activation of phospholipases. One such response concerns the activity of a class of kinase constituting the protein kinase C family. The production of specific molecular species of lipid second messengers may be therefore of prime importance in the activation of a member of the PKC isoforms. Prompted by this possibility we investigated the production of 1,2 diacyl-sn-glycerol (DAG) and phosphatidic acid (PtdOH) in LA-N-1 neuroblastoma cells under various physiological states. 12-0-Tetradecanoylphorbol 13-acetate (TPA) stimulation activated a phospholipase D (PLD) specific for phosphatidylcholine (PtdCho) in proliferating cells and a phospholipase C (PLC) specific for phosphatidylethanolamine (PtdEtn) in retinoic acid (RA) differentiated cells. These separate activations produced different molecular species of DAG or PtdOH. PtdOH was able to stimulate the Ca2+ dependent protein kinase C (PKC) by a mechanism which differed from the action of DAG. PtdOH did not induce the translocation of the PKC to the membrane. Moreover PtdOH, in contrast to DAG, prevented PKC degradation by inhibiting the enzymatic hydrolysis by m-calpain. These observations suggest that the stimulation of cells by agonists elicited the production of specific molecular species of lipid second messengers depending on the physiological status of the cells, and probably on the nature of the stimulus. It seems therefore likely that the generation of specific lipid second messengers may activate specific PKC isoforms resulting in a specific cellular response.
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PMID:Production and function of lipid second messengers in proliferating and differentiated neuroblastoma cells. 890 81

Treatment of HeLa cells with retinoic acid (RA) gives rise to a marked stimulation in the incorporation of [alpha-32P]GTP into an approximately 87-kDa cytosolic protein that cross-reacts with a monoclonal antibody raised against tissue transglutaminases. In the absence of RA treatment, the transglutaminase immunoreactivity elutes from a gel filtration column with an apparent size of approximately 600 kDa (designated TGa), whereas following RA treatment, a second peak of transglutaminase immunoreactivity (designated TGb) is detected with an apparent size of approximately 150 kDa. The TGa fractions show little or no GTP-binding or GTP hydrolytic activity and very little transglutaminase activity. However, the TGb fractions show all three activities. Retinoic acid treatment also promotes the association of the GTP-binding protein/transglutaminase with membrane fractions, as detected by Western blotting and photoaffinity cross-linking with [alpha-32P]GTP. In addition, the TGb fraction shows a markedly enhanced ability (relative to TGa) to associate with membranes from control (non-RA-treated) cells. The ability of the GTP-binding protein/transglutaminase to bind to membranes is correlated with the stimulation of a membrane-associated phospholipase C activity. Thus, these findings indicate that RA treatment results in a number of changes in the biochemical properties of a GTP-binding protein/transglutaminase which strongly enhance its ability to bind GTP, associate with plasma membranes, and stimulate phosphoinositide lipid turnover.
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PMID:Biochemical effects of retinoic acid on GTP-binding Protein/Transglutaminases in HeLa cells. Stimulation of GTP-binding and transglutaminase activity, membrane association, and phosphatidylinositol lipid turnover. 891 Mar 4

In the fly, thorough retinoid deprivation is possible, to optimize investigation of the effects of vitamin A metabolites and retinoic acid (RA) on visual development. Retinoids had been found to control fly opsin gene transcription, though this finding was contested. Northern blots on Drosophila heads showed that mRNA of Rh1 (the predominant rhodopsin) was high in vitamin A replete controls, very low in deprived flies, and increased upon feeding carrot juice to deprived flies as early as 1 hr. Expression of the ribosomal protein 49 [rp49] gene (the control) was equal both in deprivation and in replacement. Recovery of Rh1 protein upon such carotenoid replacement followed, barely detectable on Western blots at 4 hr but conspicuous by 8 hr. Alternative chromophore deprivation with yeast-glucose food yielded flies with opsin mRNA on Northerns but not rhodopsin, as demonstrated by Western blots, spectrophotometry and the electroretinogram (ERG). Rh1's mRNA but not Rh1 protein resulted from rearing flies from egg to adult on the otherwise deprivational medium supplemented with RA or beef brain-heart infusion. By comparing results from these different media it was concluded that: [1] deprivation and replacement affect opsin gene transcription; and [2] contradictory conclusions were from chromophore deprivation which does not eliminate all retinoid dependent factors which could affect the opsin promoter. Preliminary evidence shows that carotenoid deprivation decreases two proteins relevant to visual function: [1] phospholipase C (PLC); and [2] Drosophila retinoid binding protein (DRBP).
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PMID:Control of Drosophila opsin gene expression by carotenoids and retinoic acid: northern and western analyses. 899 52

The biological significance of phosphatidylcholine-specific phospholipase C (PC-PLC) in hepatocarcinogenesis and the proliferation and differentiation of rat liver cancer cells was investigated. The Ca2+-dependent activities of PC-PLC gradually increased during N-nitrosodiethylamine (DEN)-induced hepatocarcinogenesis and peaked at weeks 18-20 when the tumour formed. There was a close relationship between Ca2+-dependent PC-PLC activities and cellular DNA content, membranous gamma-glutamyltranspeptidase (gamma-GT), and tyrosine protein kinase. In contrast, Ca2+-independent PC-PLC activities decreased during hepatocarcinogenesis. Similarly, when CBRH-7919 rat liver cancer cells were treated with phorbol 12-myristate 13-acetate, a proliferation stimulator of the cells, gamma-GT and Ca2+-dependent activities of PC-PLC and the expression of alpha-fetoprotein increased significantly. However, when these cells were induced by retinoic acid to differentiate, Ca2+-dependent PC-PLC and gamma-GT activities decreased significantly, together with alpha-fetoprotein expression. There was a close relationship between Ca2+-dependent PC-PLC and gamma-GT activities during differentiation as there was during proliferation. We suppose that Ca2+-dependent PC-PLC is involved in rat hepatocarcinogenesis induced by DEN and that it plays an important role in the phorbol ester-induced proliferation or retinoic acid-induced differentiation of liver cancer cells.
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PMID:Changes of phosphatidylcholine-specific phospholipase C in hepatocarcinogenesis and in the proliferation and differentiation of rat liver cancer cells. 926 91

Release of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) generated by phospholipase C (PLC) upon receptor stimulation plays an important role in the regulation of cell growth and differentiation. A second, completely different, signal transduction system involves retinoic acid (RA) and related derivatives. Binding to intracellular receptor sites can modulate keratinocyte growth and inhibits differentiation. The present study was aimed at characterizing possible interactions between the two signalling pathways in HaCaT keratinocytes. As determined by anion exchange chromatography and HPLC analysis, HaCaT keratinocytes treated with 1 microM RA for up to 72 h showed a marked decrease in Ins(1,4,5)P3 release upon stimulation with 10 microM bradykinin or 10 microM ionomycin. Thin-layer chromatography of phosphatidylinositol phosphates, the substrates of PLC, revealed no differences between RA-treated and untreated cells. Western blot analysis of the PLC isozymes present in HaCaT cells, PLC beta 3 and PLC gamma 1, showed no alterations in the expression of these proteins in RA-treated cells as compared to vehicle-treated controls. In addition, expression of the PLC-activating G protein G alpha q was not affected by RA treatment. Our results show that RA downregulates the PLC-mediated signaling system. The point of interference of this signal transduction crosstalk has yet to be elucidated. Our results suggest, furthermore, that RA-induced attenuation of keratinocyte differentiation might be mediated at least in part by the downregulation of Ins(1,4,5)P3 release.
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PMID:Retinoic acid attenuates phospholipase C-mediated signaling in HaCaT keratinocytes. 934 74


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