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)

There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.
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PMID:Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. 176 Aug 77

Vascular smooth muscle cells from spontaneously hypertensive rats (SHR) were growth stimulated when cocultured with bovine aortic endothelial cells whereas myocytes from normotensive, Wistar Kyoto rats (WKY) were growth inhibited. The responsiveness of cells from the two rat sources to the two homodimeric forms of platelet-derived growth factor (PDGF-AA or -BB) was different; SHR-derived cells responding equally well to both PDGF forms whereas cells from WKY responded to the B-chain homodimer only. The responses measured included S6 kinase activation, phospholipase C mediated phosphoinositide catabolism and cell growth. Saturation binding experiments using [125I]-labelled PDGF homodimers (AA or BB) indicated that smooth muscle cells from hypertensive rats possess similar numbers of cell-surface A-chain receptors (alpha subunits) as Swiss 3T3 cells which have been used to characterize the mitogenic effects of the two PDGF homodimeric forms. The differences in responsiveness of SHR vs WKY cells to PDGF-AA and to the influence of endothelial cells may reside in their differential expression of PDGF receptors.
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PMID:Platelet-derived growth factor A-chain homodimer stimulated growth of cultured smooth muscle cells from spontaneously hypertensive rats. 177 8

The human T-cell line Jurkat was found to contain at least two immunologically distinct isoforms of inositol phospholipid-specific phospholipase C (PLC), PLC-beta 1 and PLC-gamma 1. Treatment of Jurkat cells with antibody to CD3 led to phosphorylation of PLC-gamma 1 but not of PLC-beta 1. The phosphorylation of PLC-gamma 1 occurred rapidly and transiently on both serine and tyrosine residues; tyrosine phosphorylation reached a maximum level less than 1 min after stimulation and decreased rapidly, both in the presence and in the absence of orthovanadate. Two-dimensional phosphopeptide map analysis revealed that the major sites of tyrosine and serine phosphorylation in PLC-gamma 1 from activated Jurkat cells are the same as those in PLC-gamma 1 from cells treated with peptide growth factors such as epidermal growth factor and platelet-derived growth factor. Previously, it has been shown that multiple phosphorylation of PLC-gamma 1 by the growth factor receptor tyrosine kinases leads to activation of PLC-gamma 1. Thus, the current data suggest that inositol phospholipid hydrolysis triggered by the T-cell antigen receptor-CD3 complex is due, at least in part, to activation of PLC-gamma 1 and that the mechanism by which this activation is achieved involves phosphorylation of multiple tyrosine residues on PLC-gamma 1 by a nonreceptor tyrosine kinase coupled to the T-cell antigen receptor-CD3 complex.
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PMID:CD3 stimulation causes phosphorylation of phospholipase C-gamma 1 on serine and tyrosine residues in a human T-cell line. 182 97

Several steps implicated in platelet-derived growth factor (PDGF) receptor-coupled signaling are activated by PDGF exposure at 0-4 degrees C. These include receptor self-phosphorylation, physical association with and phosphorylation of phospholipase C gamma (PLC gamma). Reduced temperature blocks PDGF internalization, making it possible to dissociate bound PDGF after PLC gamma tyrosine phosphorylation. We addressed the functional consequences of PDGF dissociation from intact cell PDGF receptors. PDGF exposure at 0-4 degrees C for 15 min stimulated self-phosphorylation of a subpopulation of BALB/c 3T3 cell PDGF beta-type receptors (35%) and initiated subsequent inositol phosphate production. A small fraction of cellular PLC gamma (1-3%) coprecipitated with ligand-activated PDGF receptors; 3-5% of cellular PLC gamma acquired phosphotyrosine. The PLC gamma coprecipitating with PDGF receptors did not contain detectible phosphotyrosine. Phosphotyrosine antibody recovered similar amounts of PLC gamma from soluble and particulate fractions of PDGF-stimulated cells. Acid dissociation of bound PDGF from receptor caused rapid dephosphorylation of PDGF receptors and PCL gamma, and interrupted PLC gamma-PDGF receptor coprecipitation. Orthovanadate blocked tyrosine dephosphorylation of both PDGF receptors and PLC gamma and stabilized coprecipitation. Orthovanadate reversed the acid wash effect to abrogate PDGF-stimulated inositol phosphate production. PDGF receptor remains competent to coprecipitate with PLC gamma and stimulate PLC-mediated inositol phosphate production if PDGF-induced receptor phosphorylation is maintained. Formation of a coprecipitable PDGF receptor-PLC gamma complex appears required for PDGF-stimulated inositol phosphate production.
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PMID:Phospholipase C gamma complexes with ligand-activated platelet-derived growth factor receptors. An intermediate implicated in phospholipase activation. 184 94

Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
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PMID:Tyrphostins inhibit PDGF-induced DNA synthesis and associated early events in smooth muscle cells. 185 Jan 95

It is known that the receptor for platelet-derived growth factor (PDGF) activates phospholipase C (PLC) by phosphorylating the gamma 1 isoform of PLC with the receptor protein-tyrosine kinase (PTK), whereas a guanine nucleotide-binding protein participates as a transducer in the PLC activation through the receptors for vasopressin, bombesin and prostaglandin F2 alpha (PGF2 alpha). We have shown in a rat fibroblast line that staurosporine is a potent PTK inhibitor capable of clearly discriminating the two types of receptor-stimulated Ca2+ mobilization and, by inference, PLC activations the response triggered by PDGF was completely inhibited, whereas the responses triggered by vasopressin, bombesin and PGF2 alpha were not affected at all. The Ca2+ mobilization in human T and B cell lines induced by anti-CD3 and anti-immunoglobulins (Ig) was completely suppressed by staurosporine. The results indicate that the PTK activity plays an essential role in the PLC activation through the T cell receptor/CD3 complex and through membrane Ig.
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PMID:Suppression by staurosporine of Ca(2+)-mobilization triggered by ligation of antigen-specific receptors on t and B lymphocytes. An essential role of protein tyrosine kinase in the signal transduction. 187 63

We describe the enzymological regulation of the formation of prostaglandin (PG) D2, PGE2, PGF2 alpha, 9 alpha, 11 beta-PGF2, PGI2 (prostacyclin), and thromboxane (Tx) A2 from arachidonic acid. We discuss the three major steps in prostanoid formation: (a) arachidonate mobilization from monophosphatidylinositol involving phospholipase C, diglyceride lipase, and monoglyceride lipase and from phosphatidylcholine involving phospholipase A2; (b) formation of prostaglandin endoperoxides (PGG2 and PGH2) catalyzed by the cyclooxygenase and peroxidase activities of PGH synthase; and (c) synthesis of PGD2, PGE2, PGF2 alpha, 9 alpha, 11 beta-PGF2, PGI2, and TxA2 from PGH2. We also include information on the roles of aspirin and other nonsteroidal anti-inflammatory drugs, dexamethasone and other anti-inflammatory steroids, platelet-derived growth factor (PDGF), and interleukin-1 in prostaglandin metabolism.
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PMID:Prostaglandin and thromboxane biosynthesis. 190 23

Thrombin is present in high concentrations at sites of clots and may have important post-clotting effects on adjacent vascular tissue. This may be particularly important for vascular smooth-muscle cells (VSMC), whose growth and contractility are altered following atherosclerotic-associated thromboses. To study the cellular signal events by which thrombin exerts its actions, the effects of purified human alpha-thrombin were examined in cultured rat aortic VSMC. alpha-Thrombin stimulated a biphasic change in intracellular pH (pHi), causing an early rapid acidification, followed by a sustained alkalinization. The increase in pHi was dependent on extracellular Na+ and inhibited by 5'-(NN-dimethyl)amiloride, consistent with mediation by Na+/H+ exchange. alpha-Thrombin rapidly increased free intracellular [Ca2+] ([Ca2+]i). The increase in [Ca2+]i was secondary to activation of phospholipase C, as demonstrated by increases in InsP3 (226%) and InsP2 (387%) and decreases in polyphosphoinositides at 15 s. Expression of the mRNA for the proto-oncogene c-fos was induced by alpha-thrombin. Stimulation of c-fos mRNA was not dependent on alterations in pHi, but required a rise in [Ca2+]i. Despite many growth-related signals shared by alpha-thrombin with platelet-derived growth factor, alpha-thrombin failed to stimulate [3H]thymidine incorporation or cell division, although there was a maximal increase of 52% in protein synthesis. The data suggest that there are cellular signal events not activated by alpha-thrombin which are required for proliferation of these aortic VSMC.
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PMID:Thrombin-stimulated events in cultured vascular smooth-muscle cells. 201 7

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

Endothelin, a 17-DKa peptide originally described as a potent vasoconstrictor, also stimulates the release of important regulators of glomerular hemodynamics such as atrial natriuretic factor and renin. In the present study we investigated the role of endothelin in the release of another potent vasoconstrictor and mitogen of human mesangial cells, the platelet-derived growth factor. Endothelin stimulated PDGF release at 12 hours and the effect was sustained for 36 hours. This effect was associated with the enhanced induction of mRNAs encoding PDGF A- and B-chain. Endothelin also induced mitogenesis in human mesangial cells which was accompanied by activation of phospholipase C with increased inositol phosphate turnover. These data suggest a mechanism by which endothelin may regulate mesangial cell function in disease states.
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PMID:Endothelin stimulates PDGF secretion in cultured human mesangial cells. 207 61


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