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)

It is now generally considered that early signalling from tyrosine kinases that induce mitogenesis is initiated through the formation of heteromeric complexes consisting of the autophosphorylated tyrosine kinase and a number of tyrosylphosphorylated proteins, including phospholipase C-gamma (PLC-gamma) and GTPase activating protein (GAP). However, since much of this work has been performed on proliferative, chimeric cell lines expressing heterologous receptor molecules, we examined the nature of the epidermal growth factor receptor (EGFR) signalling complex formation in the human breast cancer cell line, MDA-468. This cell line has an amplified, native EGFR gene, correspondingly overexpresses the EGFR, and its growth in culture is inversely related to the EGF concentration. Our results indicate that in MDA-468 cells, both the EGFR and PLC-gamma are phosphorylated on tyrosine residues and can be co-immunoprecipitated. This occurs at both high and low EGF concentrations regardless of the proliferative endpoint. The molecular association is correlated with a significant increase in total inositol phosphates formed in response to the growth factor treatment. In contrast, however, there is no evidence that GAP is either phosphorylated on tyrosine residues or forms a complex with the activated EGFR in EGF-treated MDA-468 cells. These observations suggest that as a model for growth factor action, the formation of heteromeric protein signalling complexes may demonstrate considerable diversity depending upon both cell type and physiology.
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PMID:Atypical receptor-mediated signal transduction events in the EGF-dependent growth-inhibited cell line, MDA-468. 133 Nov 23

The neu/erbB-2 protooncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential of the presumed receptor is released through multiple genetic mechanisms including a point mutation, truncation of non-catalytic sequences and overexpression. The latter mechanism appears to be relevant to human cancers as elevated expression of the neu/erbB-2 gene is frequently observed in solid tumors of various adenocarcinomas. It is therefore conceivable that strategies aimed at the biochemical mechanism of action of the neu/erbB-2 tyrosine kinase may contribute to the treatment of certain human cancers. To this aim we undertook a multiple research approach consisting of the following directions: (i) The neu/erbB-2 ligand--a systematic screening of potential biological sources of the hypothetical hormone molecule, that presumably binds to the neu/erbB-2 protein, resulted in detection of a candidate activity in the medium of certain cultured transformed cells. Partial purification indicated that the factor is a 30-35 kDa glycoprotein. Further studies revealed several biochemical characteristics of the factor that may be helpful for complete purification and structural analysis of this novel hormone. (ii) Signal transduction by neu/erbB-2--using a chimeric receptor approach and various mutants we found that all the oncogenic forms of the neu/erbB-2 are constitutively coupled, both physically and functionally, to a multi-protein complex of signaling molecules. The latter includes the phosphatidylinositol-specific phospholipase C gamma and a phosphatidylinositol kinase. Thus, the metabolism of inositol lipids is probably a major biochemical pathway utilized by the neu/erbB-2 tyrosine kinase. (iii) Tumor inhibitory antibodies--we generated a panel of monoclonal antibodies to the presumed receptor. Surprisingly, some antibodies almost completely inhibited the growth of tumor cells in athymic mice, whereas one antibody significantly accelerated the rate of tumor growth in animals. Interestingly, the inhibitory antibodies conferred a mature phenotype to cultured breast cancer cells, implicating terminal differentiation in tumor retardation.
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PMID:Signal transduction by the neu/erbB-2 receptor: a potential target for anti-tumor therapy. 135 18

Members of the bombesin-related family of peptides (BRPs) are mitogenic for a variety of cell types; however, a role for these peptides has not been previously described in human breast cancer. Early membrane receptor signal transduction mechanisms associated with bombesin action include phospholipase C-mediated inositol phospholipid hydrolysis and the elevation of cytosolic Ca2+ levels. We have investigated a potential role for BRPs in breast cancer by studying their effect on phospholipid hydrolysis, 45Ca2+ efflux, and cell growth in the human breast cancer cell line MCF-7. Bombesin stimulated a dose-dependent increase in the hydrolysis product inositol monophosphate during 1 h with a half-maximal effect around 1 nM. A transient increase in inositol trisphosphate in response to bombesin was also apparent at 2 min. Two distinct bombesin receptor antagonists inhibited this bombesin-induced phospholipid hydrolysis. Both bombesin- and gastrin-releasing peptide also stimulated a dose-related increase in inositol phosphate production in T47D cells, a different human breast cancer cell line. The efflux of 45Ca2+ from prelabeled MCF-7 cells was also stimulated by bombesin. This apparent cellular Ca2+ mobilization was partly dependent on extracellular Ca2+ and was inhibited by Ni2+. Despite this activation of putative mitogenic signaling pathways, bombesin had no effect on either proliferation or DNA synthesis in MCF-7 cells. These data implicate a functional role for BRPs in human breast cancer.
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PMID:Activation of inositol phospholipid signaling and Ca2+ efflux in human breast cancer cells by bombesin. 215 48

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

Lithium-stimulated MCF-7 cell proliferation was compared to proliferation stimulated by other mitogens for this cell line-estradiol (E2) and epidermal growth factor (EGF)-and lithium was found to be effective within a narrow concentration range. Mitogenic effects of lithium on proliferation stimulated by E2 and EGF were additive below maximum, but were not synergistic. The phosphoinositide pathway is a cell signaling system involved in cell proliferation, within which phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] leads to the production of the second messengers inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG), as well as to calcium mobilization. At mitogen concentrations which maximally stimulated cell growth, estradiol stimulated both growth and PLC activity, while EGF and lithium stimulated cell growth but had little effect on the activity of the enzyme. Dose-responses with EGF revealed that a low concentration (0.1 ng/ml, 0.017 nM) of EGF appeared to stimulate both PLC activity and cell growth, but that higher concentrations of EGF which stimulated greater proliferation inhibited PLC activity. Steady-state levels of inositol phosphates including inositol trisphosphate were increased by all three mitogens. In growth assays, the phorbol ester phorbol 12-myristate-13-acetate (PMA), which mimics the actions of DAG, stimulated some cell growth, but dioctanoylglycerol, an additional DAG analog, and the calcium ionophore A23187, alone or with the DAG analogs, had no effect. These results suggest that PLC-mediated PtdIns(4,5)P2 hydrolysis is not primarily associated with signaling proliferation by lithium or EGF in MCF-7 breast cancer cells.
Breast Cancer Res Treat 1995 Jun
PMID:Relationship of growth stimulated by lithium, estradiol, and EGF to phospholipase C activity in MCF-7 human breast cancer cells. 757 91

The phosphorylation of P-glycoprotein has been appreciated for many years, yet little is known about the factors that initiate this post-translational modification. To determine whether the activation of P-glycoprotein phosphorylation could occur in response to cellular stress and to investigate the possible signal pathways involved, we studied the effect of heat shock on the phosphorylation of P-glycoprotein in sensitive and resistant MCF-7 human breast cancer cells. Treatment of multidrug resistant MCF-7/AdrR cells with heat shock increased the phosphorylation of P-glycoprotein. The response was not seen in the sensitive MCF-7 line, which does not express this drug transporter. Phosphorylation of P-glycoprotein induced by heat shock was not dependent on synthesis of new proteins, since phosphorylation was not inhibited by cycloheximide and the content of P-glycoprotein, as measured by immunoblotting, did not change after heat shock. The activation of P-glycoprotein phosphorylation by heat shock may be initiated through activation of phospholipase C, since heat shock stimulated the activity of this enzyme, as evidenced by increased formation of inositol trisphosphate and diacylglycerol and by phosphorylation of phospholipase C-gamma. U-73122, an inhibitor of phospholipase C and staurosporine, an inhibitor of protein kinase C, both decreased the heat-shock-induced phosphorylation of P-glycoprotein. These results suggest that heat shock induces phosphorylation of P-glycoprotein through the activation of the phospholipase C/protein kinase C pathway.
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PMID:Involvement of phospholipase C in heat-shock-induced phosphorylation of P-glycoprotein in multidrug resistant human breast cancer cells. 774 43

Bombesin (BBS) and its mammalian equivalent, gastrin-releasing peptide (GRP), exhibit diverse biological functions, including that of a neurotransmitter, a regulator of gastrointestinal hormone release, and a trophic factor for various normal and neoplastic tissues. Bombesin stimulates the growth of normal cells of the stomach, pancreas, and bronchial epithelium as well as cells in breast cancer, gastrinoma, and small cell lung cancer. The purpose of this study was to determine whether BBS regulates the growth of a human gastric cancer cell line (SIIA) in vitro, and if so, to examine the mechanisms of signal-transduction that are involved. We found that BBS stimulated the growth of SIIA cells in vitro. The GRP receptor antagonists, BIM 26189 and BIM 26226, had no effect on growth of SIIA cells. Although these antagonists blocked the BBS-induced increase of [Ca2+]i, they failed to block the growth-stimulatory effect of BBS. BBS stimulated intracellular tyrosine phosphorylation of multiple proteins, with a predominant protein of apparent molecular weight of 125 kDa. Inhibition of intracellular tyrosine kinases by tyrphostin blocked the growth-stimulatory effect of BBS on SIIA cells. These results indicate that BBS exerts its trophic effect on SIIA cells through a receptor(s) linked to tyrosine kinase pathway, but not to the phospholipase C (PLC) pathway.
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PMID:Bombesin stimulates the in vitro growth of a human gastric cancer cell line. 796 32

Activity of the enzyme phosphatidylinositol 4,5-bisphosphate phospholipase C (PIP2-PLC) was demonstrated in MCF-7 human breast cancer cell homogenate. The addition of 10(-9) M 17 beta-estradiol to the culture medium elicited in the cells two types of responses depending on the period of exposure. Enzyme activity was rapidly activated at 15 s of incubation. After 5 min, PIP2-PLC activity was inhibited, and this effect continued at least until 24 h of exposure to the hormone. When 17 beta-estradiol was added in vitro to the total homogenate of untreated cells, enzyme activity was stimulated in a dose-dependent manner. These findings indicate that 17 beta-estradiol induces early and long-term modifications of the phosphoinositide signal pathway in intact MCF-7 cells as well as in vitro. The rapidity of the early effect suggests a non-genomic action of estradiol.
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PMID:Rapid and long-term effects of 17 beta-estradiol on PIP2-phospholipase C-specific activity of MCF-7 cells. 838 2

The antiestrogen tamoxifen is widely used for endocrine therapy of breast cancer; however, the mechanisms of estrogen receptor-independent interactions of tamoxifen remain ill defined. Here we examine the effect of tamoxifen on the initial steps of cell signal transduction. To this end, phospholipid metabolism and protein kinase C (PKC) translocation were assessed in CCD986SK human mammary fibroblasts treated with tamoxifen. The addition of tamoxifen resulted in dose-dependent and time-dependent increases in the cellular second messengers phosphatidate (PA) and diacylglycerol (DG). On addition of ethanol to the medium, tamoxifen induced the formation of phosphatidylethanol, demonstrating that tamoxifen activates phospholipase D (PLD). Cellular DG also increased in the presence of ethanol, showing that tamoxifen also activates phospholipase C (PLC). In cells prelabeled with choline and ethanolamine, tamoxifen caused increases in choline, phosphorylcholine, ethanolamine and phosphorylethanolamine. Structure-activity relationship studies for activation of PLD revealed that tamoxifen was the most effective, whereas 4-hydroxy tamoxifen was nearly devoid of activity. Phorbol diesters also activated PLD, but estrogen had no influence. Pretreatment of cells with phorbol dibutyrate (PKC down-regulation protocol) blocked phorbol diester- and tamoxifen-induced PLD activity. Exposure of cells to the PKC inhibitor GF 109203X diminished tamoxifen-induced PLD activity. Addition of tamoxifen to cultures elicited selective membrane association of PKC epsilon. We conclude that tamoxifen exerts considerable extra-nuclear influence at the transmembrane signaling level. These events may contribute to effects beyond the scope of estrogen receptor-dependent actions.
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PMID:Tamoxifen activates cellular phospholipase C and D and elicits protein kinase C translocation. 905 57

Mab B21 is a monoclonal antibody (Mab) that recognizes an epithelial tumor surface antigen (ETSA-B21) from diverse human tumor cell lines including breast, ovary, uterus, and their cognate carcinoma tissues. A lower reactivity has been observed in normal breast tissue and benign hyperplesia. In this study, the characteristics of the ETSA-B21 antigen have been examined in greater detail in the MCF-7, SK-BR-3, and MDA-MB-453 breast cancer cell lines. Treatment with phosphatidylinositol-phospholipase C, but no neuraminidase were found to partially remove the ETSA-B21 signal from the cell surface as revealed by immunofluorescence microscopy. Inhibition of the N-glycosylation pathway by tunicamycin resulted in a decreased ETSA-B21 signal on the cell membrane. In addition, the antigen-antibody complex was internalized in breast cancer cells as demonstrated by an acidic was internalization assay evaluated using immunofluorescence. In conclusion, this study suggests that ETSA-B21 is a GPI anchor N-glycosylated protein promoting specific antibody internalization in breast cancer cells.
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PMID:Characterization of the ETSA-21 antigen, a glycosylphosphatidyl-inositol anchor glycoprotein identified in breast cancer cells using monoclonal antibody B21. 914 15


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