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)

Previous studies showed that the human monocytic leukemia cell line THP-1 can be induced to undergo monocytic differentiation by tumor promoting phorbol esters (TPA), suggesting that protein kinase C (PK-C), the primary binding site of TPA, may play a role in the control of monocytic differentiation: The effect of exogenous phospholipase C (PLC) on THP-1 cells was investigated. Within 24-48 hr, PLC induced over 40% of THP-1 cells to undergo monocytic differentiation as manifested by adherence, growth arrest, functional expression, morphological changes and expression of c-fms gene which encode for M-CSF receptors. Compared to TPA, however, the inducing activity of PLC was weaker, slower and not as effective. PLC treatment also induced a transient expression of c-fos proto-oncogene prior to c-fms expression. On the contrary, the level of c-myc RNA, which is constitutively expressed in THP-1 cells, was down-regulated 48 hr after PLC treatment. The PLC-induced monocytic differentiation in THP-1 cells was inhibited by staurosporine, a potent PK-C inhibitor, further suggesting that direct activation of the PK-C is one of the metabolic events essential for monocytic differentiation. It is postulated that in THP-1 cells the metabolic pathway transducing PK-C activation has been permanently blocked, thereby leading to uncontrolled proliferation without differentiation.
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PMID:Phospholipase C-induced monocytic differentiation in a human monocytic leukemia cell line THP-1. 149 32

Interleukin-2 (IL-2) plays a central role in the immune system by regulating the proliferation and differentiation of T lymphocytes. However, the molecular mechanism of the signal transduction through the IL-2 receptor is poorly understood. We have studied the role of phosphatidic acid (PA) on IL-2 signal transduction using cloned T lymphocytes. IL-2 stimulated a transient increase in the PA concentration in resting CTLL-2 cells prelabeled with [3H]palmitic acid. This effect was detected as early as 1 min after IL-2 addition and peaked at 5 min. IL-2 similarly increased phospholipase D activity in intact CTLL-2 cells, as inferred by phosphatidylethanol production. By contrast, IL-2 did not affect [3H]palmitic acid-labeled diacylglycerol levels. Furthermore, exogenous addition of several natural or synthetic PA to T cells mimicked IL-2 activity. Thus, PA were able to induce DNA synthesis on CTLL-2 cells, although this effect was only 10%-20% of that observed with IL-2. PA showed a synergistic effect with low doses of IL-2. In addition, PA was able to induce c-myc RNA transcription in CTLL-2 cells as well as IL-2 receptor (CD25) expression on the cell membrane with equal potency as saturating doses of IL-2. It is likely that IL-2-induced PA accumulation is a consequence of phospholipase D activation. This hypothesis is further supported by the fact that the addition of exogenous phospholipase D but not phosphatidylinositol-specific phospholipase C also reproduced the IL-2 or PA effects mentioned above. In summary, our results suggest a role of phospholipase D activation and PA formation as second messengers of IL-2 activity.
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PMID:Regulation of interleukin-2 responses by phosphatidic acid. 162 28

In order to define the molecular mechanism involved in enhancement of spontaneously hypertensive rat (SHR) cell proliferation, we have compared the actions of fetal calf serum (FCS) and angiotensin II on both SHR and Wistar-Kyoto (WKY) rat aortic smooth muscle cells. Both compounds are more mitogenic in SHR cells than in controls. However, phospholipase C (PLC) hyperresponsiveness can be seen only under angiotensin stimulation, as are the expressions of c-jun, c-fos, and c-myc. Oncogene overexpression therefore appears to be more strongly related to PLC hyperreactivity than to enhanced proliferation of SHR aortic smooth muscle cells.
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PMID:Enhanced cell proliferation in essential hypertension. 170 7

Activated p21ras alters the platelet-derived growth factor (PDGF) signal transduction pathway in fibroblasts by inhibiting autophosphorylation of the receptor as well as by inhibiting the induction of the growth-related genes c-myc, c-fos, and JE. To elucidate the cause and effect relationships between receptor autophosphorylation and other second messenger events in the PDGF signaling pathway we created revertants of v-ras transformed cells by two methods: 1) the use of cAMP analogues, and 2) the introduction of a gene, Krev-1, which has been reported previously to revert ras transformed cells to normal morphology. Analysis of the revertants shows that the PDGF-mediated tyrosine phosphorylation of the 180-kDa PDGF receptor remains inhibited; however, the PDGF-mediated activation of phospholipase C and the induction of the growth-related genes c-myc, c-fos, and JE have been restored. These data suggest the presence of parallel pathways for PDGF signal transduction which are not dependent on autophosphorylation of the PDGF receptor.
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PMID:Dissociation of platelet-derived growth factor (PDGF) receptor autophosphorylation from other PDGF-mediated second messenger events. 171 14

Changes in the [Ca2+]i and/or activation of phospholipase C are thought to participate in the control by several growth factors of the mammalian cell proliferation. It has even been claimed that activation of the Ca(2+)-phosphatidylinositol cascade is sufficient to elicit cell proliferation [Jackson et al. (1988) Nature 335, 437-440; Julius et al. (1989) Science 244, 1057-1062]. In this work, we have evaluated the control of DNA synthesis by this cascade in a differentiated epithelial cell model: the dog thyrocyte in primary culture. We first observed that potent activators of the dog thyrocyte (2+)-phosphatidylinositol cascade such as carbachol or bradykinin failed to promote the onset of DNA synthesis in these cells. Moreover, carbachol inhibited the mitogenic effect of thyroid stimulating hormone (TSH) and of epidermal growth factor (EGF). The mitogenic effect of EGF was also reduced by bradykinin. Nevertheless, carbachol enhanced the expression of the protooncogenes c-fos and c-myc mRNAs. The time course of this enhancement was identical to the time course for the induction of c-fos and c-myc mRNAs by phorbol esters or EGF. On the other hand, in most experiments, TSH and EGF were able to trigger the onset of dog thyrocyte DNA synthesis without affecting their intracellular free Ca2+ concentration [Ca2+]i, 45Ca2+ efflux, or inositol phosphate generation. In several experiments, TSH increased the dog thyrocyte 45Ca2+ release and promoted a rise in the [Ca2+]i or the inositol phosphate accumulation but these effects were weak. In contrast to the effect of carbachol, the TSH effects on the [Ca2+]i and the 45Ca2+ efflux appeared slowly, were sustained, and were extremely sensitive to extracellular Ca2+ depletion. They were observed at hormone concentrations higher than the concentration achieving maximal stimulation of DNA synthesis. Similarly, in a few experiments, a slight increase in the [Ca2+]i or in the inositol trisphosphate generation were provoked by EGF. However, these modifications were not associated with an increased mitogenic potency of EGF. Finally, in all experiments, fetal calf serum slightly accelerated the dog thyrocyte 45Ca2+ efflux and increased their inositol phosphate generation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lack of correlation between the activation of the Ca(2+)-phosphatidylinositol cascade and the regulation of DNA synthesis in the dog thymocyte. 172 52

Using a model of cycloheximide (CHI)-induced expression of nuclear oncogens, a comparative study of metabolism of the major lipid classes in rat liver nuclei and cells was carried out. A short-term activation of sphingomyelinase which preceded on a time scale the maximal accumulation of c-fos and c-myc transcripts was observed both in the cells and in the nuclei. In contrast with the whole cell, the level of phospholipase C activity in the nuclei did not change under conditions of oncogene activation. It was found that the maximal expression of nuclear oncogens coincided in time with cyclic changes in the content of practically all phospholipids and neutral lipids with simultaneous activation of their synthesis both in the cells and in the nuclei. However, in the nuclei the sphingomyelin metabolism activation was predominant. It is concluded that in the nucleus sphingomyelin and its metabolites may influence oncogene expression via nuclear protein kinase C.
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PMID:[Comparison of lipid metabolism in rat liver cells and nuclei during cycloheximide-induced superinduction of nuclear oncogenes]. 174 15

In chronic models of hypertension such as the spontaneously hypertensive rat (SHR), thickening of the media of large arteries occurs mainly through smooth muscle cell (SMC) hypertrophy accompanied by DNA replication resulting in large polyploid cells. In resistance vessels of SHR, medial hypertrophy occurs through a hyperplastic response. It has been suggested that this hyperplasia is due to mitogens such as platelet-derived growth factor (PDGF), while the hypertrophied polyploid cells occur from stimulation by angiotensin II from within the vessel wall. Angiotensin II activates many of the same cellular pathways as PDGF, including stimulation of phospholipase C, mobilization of intracellular calcium and activation of Na+/H+ exchange. Both induce transient increases in the proto-oncogenes c-fos and c-myc. However, a possible explanation for the difference in SMC response may be involvement of an intracellular pathway stimulated by PDGF (but not by angiotensin II), such as stimulation of JE (a cytokine-like molecule), which may activate transcriptional events necessary for mitogenesis. In atherosclerosis vascular hypertrophy occurs in the form of focal intimal thickening and results from hyperplasia of diploid SMC and their greatly increased production of extracellular matrix, (particularly collagen) and the accumulation of intra- and extracellular lipid. The SMC involved in atherogenesis are phenotypically modified compared with the SMC of undiseased regions, and amongst other features have a lower volume fraction of myofilaments (Vvmyo). Associated with modulation to a low Vvmyo are increases in SMC expression of mRNA for collagens type I (alpha 1 and alpha 2) and type III (alpha 1), elastin, fibronectin, as well as massive increases in collagen protein (26- to 45-fold), glycosaminoglycans (5-fold), and lipid accumulation (7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of vascular hypertrophy. 203 94

In order to evaluate the role of phosphoinositide turnover in growth factor action, we expressed human M1 muscarinic acetylcholine (Hm1) receptors in Chinese hamster lung fibroblasts (CCL39 cell line). In the transfected cells (39M1-81 clone), but not in wild type fibroblasts, the muscarinic agonist carbachol induced a release of inositol phosphates as strong as alpha-thrombin, a very potent growth factor and activator of phosphoinositide-specific phospholipase C (PLC) in this cell system. In contrast to thrombin, carbachol-stimulated PLC activity was not inhibited by pertussis toxin treatment of cells. At concentrations that elicited a comparable initial rate of inositol phosphate release (10 nM for thrombin and 0.1 mM for carbachol), both agents gave rise to an identical calcium signal and equally stimulated Na+/H+ exchange and the transcription of the early genes c-jun, c-fos, and c-myc. Surprisingly, however, carbachol is not a mitogen for 39M1-81 cells, and even if tested in association with insulin or fibroblast growth factor, its effects on cell proliferation remained weak when compared with thrombin. Also, the muscarinic agonist did not stimulate soft agar colony forming capacity and did not prevent growth arrest in Go upon serum deprivation of cycling 39M1-81 cells. The failure of carbachol to induce cell proliferation could not be attributed to rapid and complete desensitization of Hm1 receptors nor to the activation of inhibitory pathways like adenylyl cyclase stimulation. We conclude that strong and persistent activation of phosphoinositide turnover elicits early biochemical events generally associated with mitogenesis, but is not sufficient to stimulate or maintain continuous cell proliferation. On the basis of our results, we postulate that thrombin mitogenesis depends critically on signaling events different from phosphoinositide turnover, possibly the stimulation of a receptor tyrosine kinase or a Gi protein-activated tyrosine kinase.
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PMID:Strong and persistent activation of inositol lipid breakdown induces early mitogenic events but not Go to S phase progression in hamster fibroblasts. Comparison of thrombin and carbachol action in cells expressing M1 muscarinic acetylcholine receptors. 217 13

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.
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PMID:Lipid peroxidation and cancer: a critical reconsideration. 251 Mar 83

In order to define the molecular mechanisms involved in the hypertrophy of the arterial walls observed in essential hypertension, vascular smooth muscle cells were isolated from aortas of spontaneously hypertensive (SHR) and control (WKY) rats, and cultured (until the 4th sub-culture) in the presence of growth factors (foetal calf serum: FCS) and various vasoactive drugs. Growth rate was determined by cell counting and measurement of nuclear thymidine incorporation, and activation of phospholipase C by measurement of the inositol phosphates formed from preincorporated tritiated myo-inositol; the expression of the cellular oncogenes, c-fos and c-myc was visualized by hybridization of Northern blots performed from total RNA. In the presence of low concentrations of FCS (2 p. 100, 5 p. 100) angiotensin II (10(-7)M) and bradykinin (3 X 10(-6)M) increase the growth of both kind of cells. The inositol phosphate formation and the expression of c-fos and c-myc are also dose-dependently stimulated by these vasoactive drugs, and the cultures from SHR are more responsive than those from WKY rats. Phospholipase C hyperreactivity therefore appears to be involved in the increased proliferative ability of vascular smooth muscle cells from SHR. However other molecular processes may be involved, as suggested by the growth inhibition exerted by heparin without any action on PLC activity.
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PMID:[Molecular mechanisms controlling the proliferation of aortic smooth muscle cells in spontaneously hypertensive rats]. 251 Jun 66


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