Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Cancer Metastasis Rev 1989 Dec
PMID:Biology of the protein kinase C family. 269 70

Vascular permeability factor (VPF/VEGF) is a highly conserved multifunctional cytokine that acts directly on endothelial cells (ECs) to activate phospholipase C and induce [CA2+]i transients. Two high-affinity receptors, both tyrosine kinases, have been described. VPF/VEGF has at least two important roles in tumor biology: (1) it potently increases microvascular permeability to plasma proteins, thereby modifying the tumor extracellular matrix to promote the ingrowth of fibroblasts and new blood vessels, and (2) it is a selective EC mitogen. VPF/VEGF is also involved in several other nonmalignant processes with a pathogenesis analogous to that of tumor stroma generation, including wound healing and rheumatoid arthritis.
Invasion Metastasis
PMID:Vascular permeability factor, tumor angiogenesis and stroma generation. 754 75

Intracellular signalling pathways mediating the effects of oncogenes on cell growth and transformation offer novel targets for the development of anticancer drugs. With this approach it may be sufficient to target a component of the signalling pathway activated by the oncogene rather than the oncogene product itself. Phosphatidylinositol (PtdIns) is a key component of two growth factor signalling pathways. It acts as a substrate for PtdIns specific phospholipase C (PtdInsPLC) and for PtdIns-3-kinase. In this review the antiproliferative properties of some inhibitors of PtdInsPLC and PtdIns-3-kinase are considered. There are some compounds already in clinical trial as anticancer drugs that may act by inhibiting PtdIns signalling, as well as several compounds in preclinical development. Some problems that may be encountered in developing this new class of anticancer drugs are discussed.
Cancer Metastasis Rev 1994 Mar
PMID:Inhibitors of phosphatidylinositol signalling as antiproliferative agents. 814 48

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. As secreted by tumor cells, VPF/VEGF is a 34-42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein that acts directly on endothelial cells (EC) by way of specific receptors to activate phospholipase C and induce [Ca2+]i transients. Two high affinity VPF/VEGF receptors, both tyrosine kinases, have thus far been described. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factor in vitro, and it presumably stimulates EC proliferation in vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation. VPF/VEGF is expressed in normal development and in certain normal adult organs, notably kidney, heart, adrenal gland and lung. Its functions in normal adult tissues are under investigation.
Cancer Metastasis Rev 1993 Sep
PMID:Vascular permeability factor (VPF, VEGF) in tumor biology. 828 15

Until recently, the signal transduction pathways involved in the processes of tumor growth have been poorly understood. In the present study, we investigated cell surface receptors which utilize phosphatidylinositol (Pl) turnover/Ca2+ mobilization as a signal transduction pathway to regulate cell growth in a metastatic human lung carcinoma cell line, PG. We found that purinoceptor agonists, including ATP and its analogs, and bombesin, an amphibian tetradeca-peptide of mammalian homology gastrin-releasing peptide, induced rapid transient increase of cytoplasmic-free Ca2+ in PG cells loaded with fura-2. The Ca2+ responses were derived both from release from internal stores and the opening of plasma membrane Ca2+ channels. HPLC analysis of inositol 1,4,5-triphosphate (Ins(1,4,5)P3) and its isomers showed a receptor-linked phospholipase C activation by ATP and bombesin. Although ATP and bombesin were both able to induce Pl turnover and Ca2+ mobilization in PG cells, they had differential growth regulatory effects on PG cells. Treatment with bombesin stimulated PG cell growth while treatment with ATP inhibited significantly PG cell growth. Pharmacological studies showed that the purinoceptors on PG cells were of the P2 subtype. Other hydrolysis-resistant P2 purinoceptor agonists, including ATP gamma S and AMP-PNP, were as effective as ATP in stimulating Pl turnover and Ca2+ mobilization as well as in inhibiting PG cell growth in vitro, suggesting the potential usefulness of such ATP analogs in clinical trials. Preliminary results suggest G protein involvement in the differential regulation of ATP and bombesin signal transduction pathways.
Clin Exp Metastasis 1993 Jul
PMID:Differential growth regulation of a metastatic human lung carcinoma cell line through activation of phosphatidyl inositol turnover signal transduction pathway. 831 79

Proliferation of thyroid follicular cells is controlled by three intra-cellular cascades [cAMP, inositol 1,4,5-triphosphate (IP3)/Ca2+/diacylglycerol (DAG), and tyrosine kinases] that are activated by distinct extracellular signals and receptors. We had previously generated a transgenic mouse model in which the cAMP cascade was permanently stimulated in thyroid cells by an adenosine A2a receptor (Tg-A2aR model). In the present work, we have generated a transgenic model characterized by the chronic stimulation of both adenylyl cyclase and phospholipase C in thyroid follicular cells. The bovine thyroglobulin gene promoter was used to direct the expression of a constitutively active mutant of the alpha 1B adrenergic receptor, which is known to couple to both cascades in transfected cell lines. The expression of the transgene resulted, as expected, in the activation of phospholipase C and adenylyl cyclase, as demonstrated by the direct measurement of IP3 and cAMP in thyroid tissue. The phenotype resulting from this dual stimulation included growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and the development of malignant nodules invading the capsule, muscles, and blood vessels. Differentiated metastases were found occasionally in old animals. The development of malignant lesions was more frequent and of earlier onset than in our previous Tg-A2aR model, in which only the cAMP cascade was stimulated. These observations demonstrate that the cAMP and IP3/Ca2+/DAG cascades can cooperate in vivo toward the development of thyroid follicular cell malignancies.
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PMID:Costimulation of adenylyl cyclase and phospholipase C by a mutant alpha 1B-adrenergic receptor transgene promotes malignant transformation of thyroid follicular cells. 897 26

T-cell hybridomas metastasize widely, and the extent of dissemination correlates with invasiveness in fibroblast cultures. Previously, we provided evidence that both metastasis and in vitro invasion require activation of LFA-1, induced by G-protein-transduced signals triggered by as yet unidentified factors. We show here that LFA-1-mediated adhesion of TAM2D2 T-cell hybridoma cells to ICAM-1 can in fact be induced by direct activation of G-proteins using AIF-4, to the same extent as by using PMA or Mn2+. We assessed effects of protein kinase C (PKC), tyrosine kinase (TK), PI3-kinase (PI3K), and phospholipase C (PLC) inhibitors. Both AIF-4-induced adhesion and invasion were completely blocked by the TK inhibitor genistein and partially blocked by the PI3K inhibitor wortmannin, but not influenced by PKC inhibitor GF109203X. Downregulation of PKC did not affect invasion or adhesion induced by AIF-4 either. In contrast, GF109203X and PKC downregulation blocked PMA-induced adhesion, but genistein and wortmannin had no effect. Invasion and both AIF-4- and PMA-induced adhesion were completely blocked by the PLC inhibitor U73122. Mn(2+)-induced adhesion, which was not or was only partially blocked by the other inhibitors, was delayed by U73122, and spreading of Mn(2+)-treated cells was completely prevented by U73122. However, PLC activity during adhesion was not detected. We conclude that signals required for invasion and G-protein-induced adhesion are similar and are distinct from PKC-induced adhesion, and that in all cases PLC is likely to be activated, but is probably too local and/or transient to be detected.
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PMID:Activation of G-proteins with AIF-4 induces LFA-1-mediated adhesion of T-cell hybridoma cells to ICAM-1 by signal pathways that differ from phorbol ester- and manganese-induced adhesion. 908 64

Aberrant signal transduction pathways involved in the development of metastatic disease are poorly defined in both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Neuropeptide-driven positive feedback loops stimulating cell proliferation are characteristic of SCLC. The activation of phospholipase C (PLC)-beta1 is an early and common response to stimulation of G protein-coupled receptors by these neuroendocrine growth factors. The importance of PLC-beta in neuropeptide signaling prompted us to compare PLC-beta isoform expression and activity in four independent SCLC cell lines and four independent NSCLC cell lines. We found that PLC-beta1 is more highly expressed in SCLC than in NSCLC, as indicated by Western blotting of cell lysates. All SCLC lines studied express PLC-beta1; only one of the NSCLC lines investigated showed detectable levels of the enzyme. NSCLC lines are significantly more sensitive to the antiproliferative effects of ET-18-OCH3 (edelfosine) compared with the SCLC lines, as indicated by [3H]thymidine uptake. The only SCLC cell line (NCI-H345) that is as sensitive as the NSCLC cell lines to ET-18-OCH3 also expresses uniquely low levels of PLC-beta1. The participation of PLC-beta1 in signaling by SCLC growth factor receptors is indicated by our finding that PLC-beta1 (but not PLC-beta3) coimnunoprecipitates with G(alpha)q/11 upon activation of neurotensin receptors; this association is inhibited by ET-18-OCH3. Ca2+ mobilization mediated by neurotensin receptors is also inhibited by ET-18-OCH3. The binding of GTPgammaS to G(alpha)q/11 upon treatment of SCLC cells with neurotensin is not inhibited by ET-18-OCH3. These findings indicate that ET-18-OCH3 does not interfere with G(alpha)q/11 activation but rather inhibits the association of G(alpha)q/11 with PLC-beta1. Our data suggest that PLC-beta is an important mediator of both SCLC and NSCLC proliferation. Differences in PLC-beta1 expression may be exploitable in the development of effective diagnostic and therapeutic tools.
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PMID:Small cell lung carcinoma exhibits greater phospholipase C-beta1 expression and edelfosine resistance compared with non-small cell lung carcinoma. 1082 48

Growth-stimulating pathways activated independently of their normal tissue environment are critical to the carcinogenesis and progression of lung cancer. These pathways are comprised of extracellular growth factors; their specific receptors on the cellular membrane; signal transduction cascades in the cytosol; and target molecules, including cytoskeletal proteins, metabolic regulators, and transcription factors in the nucleus. Growth factors can be divided into two groups based on their receptors: G-protein-coupled receptors and receptor tyrosine kinases. Growth factors induce clonal expansion of lung cancer cells by autocrine and/or paracrine mechanisms. Signal transduction cascades form an extremely large and complicated network with cross-talk connections. Ras, phosphatidylinositol-3-OH kinase, and phospholipase C are three key regulators involved in the network. Recent progress in our understanding of the oncoproteins functioning in the pathways has led to the development of novel therapeutic agents. Some of the most exciting results have been obtained with inhibitors of receptor tyrosine kinases. Phase I studies of epidermal growth factor-receptor inhibitors demonstrate objective responses without severe toxicity as single agents in patients with non-small-cell lung cancer refractory to conventional chemotherapy. This new strategy might lead to breakthroughs in the treatment of lung cancer with distant metastases not curable by conventional chemotherapy alone.
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PMID:Growth-stimulating pathways in lung cancer: implications for targets of therapy. 1472 Mar 64

Metastasis of breast cancer cells is the leading cause of death in breast cancer patients. Why do breast cancer cells with high metastatic potential always keep in high proliferation and migration? The endogenous signaling pathways associated with tumor metastasis remain unclear. In the present study, we address whether a link between ERK and the enzymes associated with arachidonic acid (AA) metabolism contributes to the proliferation and migration of breast cancer cells. To identify endogenous signaling pathways involved in sustaining proliferation and migration of breast cancer cells, we performed parallel studies of human breast cancer cell lines that differ in their metastatic potential. Our data showed that cell lines with high metastatic potential, including LM-MCF-7 and MDA-MB-231, exhibited significantly high, sustained levels of phosphorylated ERK (pERK) 1/2 relative to MCF-7 cells. Our findings showed that beta-catenin, cyclin D1, and survivin serve downstream effectors of pERK1/2, whereas Gi/o proteins, phospholipase C, and protein kinase C serve upstream activators of pERK1/2. In addition, AA metabolites were able to activate Gi/o proteins, phospholipase C, protein kinase C, and pERK1/2 cascades through cyclooxygenase and lipoxygenase. In contrast, activated ERK1/2 promoted AA metabolism through a positive feedback loop, which conduces to a high proliferative potential and the migration of the breast cancer cells. Together, our data provide new mechanistic insights into possible endogenous signaling metastatic signaling pathways involved in maintaining proliferation and migration of breast cancer cells.
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PMID:A positive feedback between activated extracellularly regulated kinase and cyclooxygenase/lipoxygenase maintains proliferation and migration of breast cancer cells. 1900 12


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