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)

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

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.
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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

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

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

Many multidrug-resistant (MDR) cell lines overexpress the epidermal growth factor receptor (EGFR) as well as P-glycoprotein (P-gp). However, the role of the increased EGFR in P-gp-mediated drug resistance remains unclear. Since recent studies suggest that activation of phospholipase C (PLC) could increase the phosphorylation of P-gp, and activation of the EGFR would also activate PLC, we investigated whether the effect of epidermal growth factor (EGF) on the phosphorylation of P-gp was mediated through PLC. Treatment of the human MDR breast cancer cell line, MCF-7/AdrR, with EGF increased the phosphorylation of P-gp by 20-50%. The increased phosphorylation of P-gp was accompanied by stimulation of PLC activity, as measured by the production of inositol, 1,4,5-trisphosphate and diacylglycerol, products of phosphatidylinositol-4,5-bisphosphate hydrolysis. Treatment of MDR cells with EGF also had detectable effects on P-gp function. For example, following incubation of MCF-7/AdrR cells with ECF, we observed a consistent decrease in total vinblastine (VBL) accumulation. Kinetic analysis revealed this change to be due to an increase in membrane efflux. The latter was measured by the initial uptake velocity, which was inhibited by EGF. VBL uptake measured at 0-320 sec was inhibited by 20-40%, which was associated with a similar increase in VBL efflux. EGF had no effect on drug accumulation, uptake, or efflux in sensitive MCF-7 cells. These data indicate that EGF can modulate the phosphorylation and function of P-gp, and suggest that this effect may be initiated by the activation of PLC.
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PMID:Regulation of the function of P-glycoprotein by epidermal growth factor through phospholipase C. 926 11

Ultrastructural features of the nuclear membrane envelope (ENM) and the nuclear membrane-bound heterochromatin (NMBHC) were investigated in MCF-7 human breast cancer cells by fractal morphometry. The fractal dimension D established by the box counting method proved to be effective for quantifying nuclear changes in MCF-7 cells treated with steroid hormones, namely the estrogen 17 beta-estradiol, which stimulates cell proliferation, and the glucocorticoid dexamethasone. When MCF-7 cells were briefly (5 min) cultured in the presence of 17 beta-estradiol (10(-9) M), the irregularity of the NMBHC outline was increased as documented by the increased fractal dimension D. Changes in the ultrastructural complexity of the nuclear heterochromatin were observed in concomitance with functional changes at the cell periphery, namely the modulation of the estrogen-induced activity of phospholipase C, a cell membrane-associated enzyme involved in the signal transduction pathway via phosphoinositides metabolism. Dexamethasone did not affect the in vitro proliferation, the phospholipase C activity nor the shape of the ENM of MCF-7 cells, but reduced the structural complexity of the nuclear membrane-bound heterochromatin.
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PMID:Steroid hormones modify nuclear heterochromatin structure and plasma membrane enzyme of MCF-7 cells. A combined fractal, electron microscopical and enzymatic analysis. 961 88

Annexin I is an intracellular protein in search of a function. Ex vivo it has calcium- and phospholipid-binding properties. To evaluate its role in vivo, MCF-7 cells were stably transfected with annexin I in sense or antisense orientations. In cells overexpressing annexin I, calcium release was abrogated on stimulation of purinergic or bradykinin receptors, whereas non-transfected cells or cells with down-regulated annexin I released calcium within seconds. Basal calcium and calcium stores were not affected. The impaired calcium release was paralleled by a down-regulation of the activities of phospholipase C, group II phospholipase A2, and E-cadherin with altered adhesion and enhanced tumor growth on soft agar. Significantly smaller tumors, with the histologically most differentiated cells, were observed in nude mice inoculated with cells transfected with the antisense rather than with the sense plasmid. These observations indicate that annexin I modulates cell functions by controlling intracellular calcium release. Frey, B. M., Reber, B. F. X., Vishwanath, B. S., Escher, G., Frey, F. J. Annexin I modulates cell functions by controlling intracellular calcium release.
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PMID:Annexin I modulates cell functions by controlling intracellular calcium release. 1059 71

The effects of modifying membrane fatty acid composition on cell growth, phospholipase C (PLC) and protein kinase C (PKC) activities, and prostaglandin E2 (PGE2) secretion were investigated. Hormone responsive MCF-7 human breast cancer cells were incubated in a serum-free medium containing epidermal growth factor and supplemented with physiologic concentrations (0.18-1.78 x 10(-5) M) of linoleic acid (LA) or conjugated linoleic acid (CLA). Linoleic acid stimulated cancer cell growth, while CLA was inhibitory. Supplementation with LA or CLA altered cell membrane composition. Linoleic acid stimulated PLC activity with or without GTP gamma (S), and tended to increase membrane PKC activity. However, CLA supplementation did not modify membrane PLC or PKC activity. Prostaglandin E2 secretion was not influenced by LA or CLA. These data show that growth inhibition by CLA was not mediated through PLC-, PKC- or PGE2-dependent signal transduction pathways, suggesting that another inhibitory mechanism may be involved. Although biological differences appeared to be modest (5-20% of control), the fact that LA and CLA treatment resulted in significant biological effects at physiologic concentrations is relevant, since most human cancers require years to develop.
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PMID:Modulation of MCF-7 breast cancer cell signal transduction by linoleic acid and conjugated linoleic acid in culture. 1081 Mar 38

We have demonstrated previously that D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), an isosteric phosphonate analog of phosphatidylinositol developed to inhibit inositol lipid metabolism, was unable to inhibit phosphatidylinositol (PI) 3-kinase activity. We now report the effects of the compound on other aspects of inositol metabolism. We demonstrated that C4-PI inhibits the activity of purified recombinant PI-phospholipase C-beta (PLC-beta) at all concentrations tested; it enhanced the activity of PI-PLC-gamma and PI-PLC-delta at low concentrations (10 microM), while severely inhibiting their activities at higher concentrations. In the breast cancer cell lines MCF-7 (estrogen receptor positive) and MDA-MB-468 (estrogen receptor negative), C4-PI had no effect on the uptake of D-myo-inositol but severely inhibited its incorporation into PI. In spite of the drastic decrease in PI synthesis, C4-PI did not affect the levels of inositol incorporated into phosphatidylinositol 4,5-bisphosphate (PIP2) in the cells. In vitro assays showed that C4-PI inhibited PI synthase activity (inhibition of 35% at 50 microM) but had little effect on PI 4-kinase activity (inhibition of 13% at 150 microM). C4-PI inhibited the proliferation of MCF-7 and MDA-MB-468 cell lines with IC(50) values of 12 and 18 microM. Taken together, the results suggest that the accumulation of [3H]inositol in PIP2 in cells incubated with C4-PI may be due to the inhibition of PIP2 hydrolysis in the cells with no effect on its synthesis. The role of these C4-PI-induced effects in the mechanism of growth inhibition by C4-PI remains to be established.
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PMID:Effects of a water-soluble antitumor ether phosphonoinositide, D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), on inositol lipid metabolism in breast epithelial cancer cell lines. 1123 Aug 3


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