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)

Introduction of a v-rasHa oncogene into cultured mouse keratinocytes by transduction with a defective retrovirus is sufficient to transform keratinocytes to the benign phenotype. Transduced keratinocytes overexpress TGF alpha and hyperproliferate in culture medium with 0.05 mM Ca2+. Whereas normal keratinocytes respond to elevated medium Ca2+ by cessation of proliferation and induction of terminal differentiation, v-rasHa keratinocytes are not induced to differentiate by Ca2+. We now demonstrate that v-rasHa keratinocytes have elevated basal levels of phosphatidylinositol, inositol phosphates and diacylglycerols in 0.05 mM Ca2+ medium. Basal turnover of phosphatidylcholine is not altered by the rasHa oncogene. The generation of inositol phosphates is even further stimulated in v-rasHa cells by an increase in extracellular Ca2+ or by exposure to aluminum fluoride. Thus, the v-rasHa gene product does not stimulate the inositol phospholipid pathway maximally and additional phosphatidylinositol is available for turnover in response to inducers of phospholipase C activity. TGF alpha and medium conditioned by v-rasHa keratinocytes, both of which stimulate proliferation of normal cells in 0.05 mM Ca2+, transiently increased phosphatidylinositol turnover in normal keratinocytes but did not inhibit Ca(2+)-induced terminal differentiation. In contrast, sustained elevation in basal phosphatidylinositol metabolism was produced by aluminum fluoride. Combined exposure to aluminum fluoride and exogenous TGF alpha caused hyperproliferation, resistance to Ca(2+)-induced differentiation and morphological changes identical to those of v-rasHa keratinocytes. These results provide a link between the biological consequences of v-rasHa gene expression and biochemical changes which are known to alter the keratinocyte phenotype.
Carcinogenesis 1992 Dec
PMID:Analysis of phospholipid metabolism in murine keratinocytes transformed by the v-ras oncogene: relationship of phosphatidylinositol turnover and cytokine stimulation to the transformed phenotype. 147 46

Phorbol ester tumour promoters like phorbol-12-myristate-13-acetate (PMA) and serum-derived factors inhibit growth and induce terminal differentiation in normal human and mouse keratinocytes but have a much reduced effect on their transformed counterparts. These observations may be relevant to potency of PMA and wounding as tumour promoters in mouse epidermis. Since some serum factors produced during wounding are thought to exert their effects through the production of diacylglycerol (DAG-the proposed physiological ligand for the phorbol ester receptor) from phospholipids by the activation of phospholipase C (PC) we have compared the effects of PC with PMA in cultures of normal and transformed human keratinocytes. The addition of PC from Clostridium perfringens (0.1-3.0 units/ml) to the culture medium of normal human keratinocytes produced similar morphological changes to PMA and also mimicked the effects of the phorbol ester on cloning efficiency and cornified envelope formation. Most importantly PC, like PMA, had a very weak effect on the human squamous cell carcinoma lines SCC-12B and SCC-15. All the effects of PC were abolished by boiling the enzyme. These results are discussed in relation to the proposed role of serum factors in tumour promotion by deep skin wounding and their mechanistic relationship to phorbol esters.
Carcinogenesis 1987 Jun
PMID:Phospholipase C mimics the differential effects of phorbol-12-myristate-13-acetate on the colony formation and cornification of cultured normal and transformed human keratinocytes. 244 Jun 13

Differentiation of cultured keratinocytes is regulated by the Ca2+ concentration of the culture medium. Below 0.1 mM Ca2+, a monolayer of basal cells is formed which fully differentiates in response to a rise in medium Ca2+. A role for protein kinase C in this differentiation program has been suggested because phorbol esters induce epidermal differentiation in cells grown in reduced Ca2+ medium, and exogenously added phospholipase C (which increases cellular diacylglycerol) mimics phorbol ester action. These findings suggested that the external Ca2+ signal may lead to protein kinase C activation via stimulation of cellular phospholipase C activity. The effect of the external Ca2+ signal on phospholipase C was studied in cultures prelabeled with [3H]-inositol. Within 2 min after addition of Ca2+ to 1 mM, an increase in inositol phosphates was measured. This correlated with a decrease in radiolabeled phosphoinositides, suggesting that these were the source of the increased inositol phosphates. After 3 h in 1 mM Ca2+ medium, each of the inositol phosphates remained increased to 130-140% of control levels. Inositol phosphate metabolism in neoplastic epidermal cells was quantitatively similar to normal cells in response to the Ca2+ signal. Stimulation of phosphatidylinositol (PIP) metabolism appears to be mediated by a rise in intracellular free Ca2+ because Ca2+ ionophores A23187 and ionomycin also cause a similar rise in inositol phosphate levels. Phorbol esters did not increase PIP turnover but instead stimulated phosphatidylcholine metabolism. The induction of epidermal differentiation by phorbol esters was enhanced by ionomycin, suggesting that both protein kinase C activation, elevation of intracellular calcium and PIP turnover were important components of the signal for epidermal differentiation. These results demonstrate that the second messenger system for Ca2+-mediated keratinocyte differentiation may be through a direct effect on phospholipase C activity.
Carcinogenesis 1988 Jun
PMID:Early signals for keratinocyte differentiation: role of Ca2+-mediated inositol lipid metabolism in normal and neoplastic epidermal cells. 245 3

Established human lung cancer exhibits a complex pattern of genetic changes as well as several distinct autocrine growth factor loops for regulatory peptides. The best studied example is that of gastrin-releasing peptide (GRP), the mammalian homolog of the amphibian bombesin. It is produced by up to 70% of small cell lung cancers and 10-20% of non-small cell lung cancers. GRP stimulates the growth of normal bronchial epithelium as well as that of small cell lung cancer, and its blockade with the use of antibodies or synthetic antagonists inhibits the growth of these tumors. Study of its molecular biology has revealed a complex pattern of mRNA processing which has lead to the recent isolation of a novel family of peptides termed gastrin-releasing peptide gene-associated peptides (GGAPs), present in normal and malignant human tissues. Additional efforts have been directed at characterizing the GRP receptor as well as its intracellular signaling pathways which have been reported both as G protein phospholipase C coupled events as well as activation of a membrane associated tyrosine kinase. In view of its expression in normal bronchial epithelium and its mitogenic effects on this tissue, GRP appears to play a central role in the early events of pulmonary carcinogenesis.
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PMID:Gastrin-releasing peptide (GRP, mammalian bombesin) in the pathogenesis of lung cancer. 249 Dec 57

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

Protein kinase C (PKC) is composed of a family of isozymes that transduce signals of certain hormones, growth factors, lectins, and neurotransmitters. This review addresses the role of PKC in the regulation of cellular proliferation and its disorders. PKC is directly activated in vivo by the second messenger diacylglycerol, a lipid produced by phospholipase C-catalyzed hydrolysis of phosphatidylinositol and polyphosphoinositides. Diacylglycerol activates PKC by reducing the enzyme's requirement for Ca2+. Phorbol ester tumor promoters and related agents potently activate PKC by a mechanism analogous to that of diacylglycerol, providing evidence that PKC activation is a critical event in tumor promotion. However, the role of PKC activation in tumor promotion is not entirely clear. For example, bryostatin is a potent PKC activator that antagonizes phorbol ester-mediated tumor promotion, and mezerein is a second-stage tumor promoter that potently activates PKC. In addition to studies concerned with tumor promotion, studies of oncogene action also indicate a role for PKC in carcinogenesis. A number of plasma membrane-associated oncogene products and related proteins are PKC substrates, and PKC activation leads to induction of the expression of oncogenes that code for nuclear proteins. PKC is implicated in human breast and colon carcinogenesis. Tumor-promoting bile acids activate PKC, and PKC expression studies in rat colonic epithelial cells and human breast cancer cells indicate a positive role for PKC in the proliferation of the cells. Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.
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PMID:Biology of the protein kinase C family. 269 70

The F1 progeny of a cross between 12-O-tetradecanoyl-phorbol-13-acetate (TPA) tumor promotion-sensitive SSIN mice and TPA promotion-resistant C57BL/6J mice were found to be sensitive to TPA as a tumor promoter. The tumor response was substantial, with an average of 15 papillomas per mouse and a 100% incidence following initiation with 400 nmol dimethylbenz[a]anthracene and promotion with 6.5 nmol (4 micrograms) TPA. To determine whether tumor promotability of the F1 mice correlates with other parameters believed to be associated with TPA responsiveness, oxidant generation, epidermal hyperplasia and edema were compared in the parents and F1 hybrids. The SSIN produced a strong hyperplastic response to TPA, the C57BL/6J a negligible response and the F1 hybrids a moderate response. In the SSIN, 6.5 nmol (4 micrograms) TPA caused an 18% increase in the water content of the skin (edema) while no change was seen for either the C57BL/6J or F1 hybrids. The oxidant response of the F1 hybrids to either TPA or phospholipase C was markedly less than that observed for the SSIN and was similar to the response previously observed for the C57BL/6J mice. These findings suggest that the oxidant response may not be an essential aspect of TPA tumor promotion. It may be related to the edema response, suggesting that at least this aspect of inflammation is not necessary for promotion.
Carcinogenesis 1987 Oct
PMID:Possible dissociation of the phorbol ester-induced oxidant response and tumor promotion in the F1 offspring of SSIN x C57BL/6J mice. 365 87

A fluorescent analog of phosphatidylcholine, 1-acyl-2-[N-(4-nitrobenzo-2-oxa-1,3-diazole)aminocaproyl]phosphatidyl choline (NBD-PC), was inserted into the plasma membrane of HeLa cells. Treatment of NBD-PC-labelled cells with the tumour promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), resulted in the production of fluorescent diacylglycerol, 1-acyl-2-[N-(4-nitrobenzo-2-oxa-1,3-diazole)-aminocaproyl]diacylglycerol (NBD-DG), suggesting that phorbol ester activates a PC-specific phospholipase C in these cells. Furthermore pretreatment of cells with phorbol-12,13-dibutyrate for 24 h, a process which depletes cellular protein kinase C activity, inhibited the ability of TPA to induce this effect. These results suggest that TPA stimulation of a phospholipase C specific for PC in HeLa cells is mediated via protein kinase C.
Carcinogenesis 1987 Dec
PMID:Direct evidence for phorbol ester-stimulated accumulation of diacylglycerol derived from phosphatidylcholine. 367 18

Intercellular gap-junctional communication was measured using [14C]citrulline incorporation in co-cultures of argininosuccinate lyase-deficient human fibroblasts and argininosuccinate synthetase-deficient Chinese Hamster V79 cells. As previously shown, in this system junctional communication is completely inhibited by the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In the absence of extracellular calcium, TPA inhibition was less pronounced. However, synergism with calcium ionophore A23187 could not be demonstrated. Chlorpromazine, trifluoperazine and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester partially antagonised the effect of TPA. No antagonism was demonstrable between calmidazolium and TPA. Treatment of co-cultures with exogenous phospholipase C or 1-oleoyl-2-acetylglycerol (OAG) resulted in communication inhibition, suggesting that protein kinase C activation is involved in the mechanism of phorbol ester-mediated communication inhibition. However co-cultures which had been made refractory to TPA by prolonged exposure to high concentrations remained sensitive to inhibition by phospholipase C and OAG. These results suggest either that diacylglycerol can produce other effects independent of protein kinase C activation, or that refractoriness to phorbol esters is not simply due to a decrease in the amount of protein kinase C.
Carcinogenesis 1985 Sep
PMID:Studies on the mechanism of phorbol ester-induced inhibition of intercellular junctional communication. 392 85

Within 10 min of addition of the tumor promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) to C3H/10T1/2 mouse embryo fibroblasts, there is a two-fold increase in the level of cellular 1,2-diacylglycerol levels compared to controls. This increase in 1,2-diacylglycerol is dependent on the concentration of TPA added to the cell culture medium. The ability of macrocyclic diterpenes to induce 1,2-diacylglycerol accumulation correlated with their tumor promoting activity except for mezerein. The accumulation of 1,2-diacylglycerol in response to TPA was not blocked by a concentration of cycloheximide sufficient to inhibit protein synthesis by 95%. These data support our previous suggestion that TPA activates a phospholipase C. During the same time period, TPA increased protein phosphorylation in both quiescent and growing cells. Proteins of mol. wt. approximately 50 000, 45 000, 35 000 and 27 000 are markedly phosphorylated in response to TPA in both growing and quiescent cultures. The relationship of these phosphorylated proteins to a Ca2+ phospholipid activated protein kinase remains to be determined.
Carcinogenesis 1985 Dec
PMID:Phorbol ester induced 1,2-diacylglycerol accumulation and protein phosphorylation in C3H/10T1/2 mouse embryo cells. 406 46


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