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)

Stimulation of C6 cells with endothelin-1 (ET) caused a biphasic sn-1,2-diacylglycerol (1,2-DG) generation, which occurred not only via phosphatidylinositol 4,5-P2 (PIP2) hydrolysis by specific phospholipase C action, but also through the breakdown of phosphatidylcholine (PC) induced by either PC phospholipase C or D. ET also stimulated DNA synthesis in serum-starved C6 cells. However, in the presence of 1-(5-isoquinolynylsulfonyl)-2-methylpiperazine (H-7), a protein kinase C (PKC) inhibitor, the [3H]thymidine incorporation was markedly inhibited, which was concurrent with the 1,2-DG formation: the second peak was reduced. These findings suggest that brain glial cells might be an important target for ET. In addition to other possible roles, ET may also mediate mitogenesis in the brain, presumably through a PKC-dependent activation of phospholipase C and/or D hydrolyzing PC.
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PMID:Diacylglycerol formation and DNA synthesis in endothelin-stimulated rat C6 glioma cells: the possible role of phosphatidylcholine breakdown. 202 29

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

Colony stimulating factor-1 (CSF-1) stimulates DNA synthesis in murine bone marrow-derived macrophages (BMM); however, unlike BMM, murine resident peritoneal macrophages (RPM) undergo a poor proliferative response. It has previously been shown that phosphatidylinositol-4,5-bisphosphate hydrolysis is not associated with CSF-1 action in BMM. In this report we demonstrate that, despite a lack of inositol trisphosphate generation, CSF-1 transiently elevated both [3H]myristoyl- and [3H]arachidonyl-diacylglycerol (DAG) in BMM in a dose-dependent fashion. CSF-1 failed, however, to stimulate an increase in either species of DAG in RPM. Thus, DAG could be a second messenger for the proliferative action of CSF-1 in macrophages. Other mitogenic agents, 12-0-tetradecanoyl phorbol 13-acetate (TPA) and exogenous phospholipase C, also increased BMM levels of [3H]myristoyl- and [3H]arachidonyl-DAG. The nonmitogenic agents, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) and zymosan, had different effects on the generation of either species of DAG in BMM. LPS failed to elevate either form, TNF-alpha increased only [3H]arachidonyl-DAG, while zymosan stimulated levels of both species of DAG. It therefore appears that increased diacylglycerol generation may be necessary, but perhaps not sufficient, for macrophage proliferation.
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PMID:Colony stimulating factor-1 stimulates diacylglycerol generation in murine bone marrow-derived macrophages, but not in resident peritoneal macrophages. 204 Jun 61

A Drosophila phospholipase C (PLC) gene, designated as plc-21, was isolated by screening a genomic DNA library using a cDNA for a previously isolated Drosophila PLC gene, norpA, as probe under reduced stringency hybridization conditions. The gene maps to 21C on the left arm of the second chromosome. Two proteins of 1305 and 1312 amino acids, respectively, were deduced from two classes of cDNA which were isolated. The two putative plc-21 proteins are similar in sequence and overall structure to the beta-class of PLCs found in mammals and differ from each other only by 7 amino acid residues that are present near the C terminus of one of the proteins but not the other. Hybridization of plc-21 cDNA probes to blots of poly(A)+ RNA revealed that the gene encodes a 7.0-kilobase transcript that could be detected in the head but not in the body of adult flies and a 5.6-kilobase transcript that could be detected throughout development and in both heads and bodies of adults. In situ hybridization of cDNA sequences to tissue sections showed that the gene is expressed in the neuronal cell bodies of the optic lobe, central brain, and thoracic ganglia of adults and the brain of larvae. This tissue distribution of plc-21 transcripts is identical to the distribution of transcripts from a Drosophila Go alpha-subunit gene that we reported previously.
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PMID:A Drosophila phospholipase C gene that is expressed in the central nervous system. 206 23

Several classes of growth factors can be distinguished that act through different signal transduction pathways. One class is constituted by the peptide growth factors that bind to receptors with ligand-dependent protein tyrosine kinase activity. Another class of mitogens activates a phosphoinositide-specific phospholipase C via a receptor-linked G protein. An intriguing member of this class is lysophosphatidic acid (LPA). LPA mitogenicity is not dependent on other mitogens and is blocked by pertussis toxin. LPA evokes at least three separate signalling cascades: (i) activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis; (ii) release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and (iii) activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing responses (i) and (ii), but fails to activate Gi and to stimulate DNA synthesis. Our results suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that, unexpectedly, the phosphoinositide hydrolysis pathway is neither required nor sufficient, by itself, for mitogenesis.
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PMID:Growth factor-like action of lysophosphatidic acid: mitogenic signalling mediated by G proteins. 211 27

Pseudomonas aeruginosa produces two secreted phospholipase C (PLC) enzymes. The expression of both PLCs is regulated by Pi. One of the PLCs is hemolytic, and one is nonhemolytic. Low-stringency hybridization studies suggested that the genes encoding these two PLCs shared DNA homology. This information was used to clone plcN, the gene encoding the 77-kilodalton nonhemolytic PLC, PLC-N. A fragment of plcN was used to mutate the chromosomal copy of plcN by the generation of a gene interruption mutation. This mutant produces 55% less total PLC activity than the wild type, confirming the successful cloning of plcN. plcN was sequenced and encodes a protein which is 40% identical to the hemolytic PLC (PLC-H). The majority of the homology lies within the NH2 two-thirds of the proteins, while the remaining third of the amino acid sequence of the two proteins shows very little homology. Both PLCs hydrolyze phosphatidylcholine; however, each enzyme has a distinct substrate specificity. PLC-H hydrolyzes sphingomyelin in addition to phosphatidylcholine, whereas PLC-N is active on phosphatidylserine as well as phosphatidylcholine. These studies suggest structure-function relationships between PLC activity and hemolysis.
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PMID:Molecular comparison of a nonhemolytic and a hemolytic phospholipase C from Pseudomonas aeruginosa. 212 Jan 96

Lymphocytes are shown to express a limited number of a unique category of membrane Ag, such as Thy-1, Ly-6, Ly-31, and Qa-2, that are covalently linked to the membrane phosphatidylinositol (PI). We have identified a new glycosyl-phosphatidylinositol (GPI)-anchored lymphocyte Ag, B7, by using a mAb and have determined the primary structure by cDNA cloning. B7 Ag was expressed on the majority, if not all, of the mature lymphocytes of both T and B lineages, including strongly CD3+ thymocytes, most splenic T cells, and approximately 60% of splenic IgM+ B cells, whereas the expression of B7 Ag on bone marrow cells was negligible. The expression of B7 Ag was nearly completely abolished with as little as 2 mU of PI-specific phospholipase C per ml, which did not completely eliminate Ly-6C and Thy-1 expression. Unlike the expression of other GPI-linked lymphocyte Ag, the expression of B7 was rapidly down-regulated upon the activation of T cells by mitogens or IL-2 both in vitro and in vivo. Immunoprecipitation analysis revealed that B7 Ag was an approximately 12-kDa protein. With a CDM8 expression vector, a cDNA encoding B7 Ag was cloned, and it was confirmed that the B7 Ag on cDNA-transfected cells was indeed PI-specific phospholipase C sensitive. The B7 cDNA contained an open reading frame of 222 bp including a typical N-terminal leader sequence and a characteristic sequence at the C terminus encoding hydrophobic amino acids. A computer search revealed no significant homology to any known molecule at both DNA and amino acid sequence levels. Northern blot analysis indicated that the B7 transcript was expressed on lymphohematopoietic tissues, including thymus, spleen, and bone marrow, but not on other organs, such as liver, kidney, and brain. The results indicated that B7 Ag is a new member of the GPI-anchored proteins which is selectively expressed on mature resting but not activated lymphocytes.
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PMID:Identification and gene cloning of a new phosphatidylinositol-linked antigen expressed on mature lymphocytes. Down-regulation by lymphocyte activation. 214 7

The effects of thromboxane A2 (TXA2) on the proliferation of vascular smooth muscles cells (VSMC) were examined using primary cultures of VSMC from rat aorta. U46619, a stable TXA2 mimetic, stimulated DNA synthesis of VSMC only in the presence of insulin. The effect was concentration-dependent with a half-maximal effect obtained at approximately 1 x 10(-8) M. The mitogenic effect of U46619 was larger than that of endothelin, another mitogen derived from endothelium. Among several TXA2/PGH2 analogs, the proliferative activity was detected only in the agonists, and not in the antagonists or in the metabolite of TXA2. A series of TXA2/PHG2 receptor antagonists completely suppressed the U46619-stimulated DNA synthesis as well as the [3H]SQ29,548 binding to the TXA2/PGH2 receptors in VSMC. The rank order of binding affinities to the receptors among the respective antagonists correlated well with the potencies for suppression of the proliferative effects of U46619. The mitogenic effects of U46619 were also attenuated by the presence of calcium antagonists. U46619 caused activation of phospholipase C with the production of inositol trisphosphate, leading to increases in the intracellular free Ca2+ concentration as measured with the fluorescent indicator fura-2. These results suggest that TXA2 induces mitogenic effects on VSMC through binding to its specific receptors. This effect of TXA2 on the proliferation of VSMC may be related to the development of atherosclerosis.
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PMID:Receptor-mediated mitogenic effect of thromboxane A2 in vascular smooth muscle cells. 214 80

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

Regions of the hamster alpha 1-adrenergic receptor (alpha 1 AR) that are important in GTP-binding protein (G protein)-mediated activation of phospholipase C were determined by studying the biological functions of mutant receptors constructed by recombinant DNA techniques. A chimeric receptor consisting of the beta 2-adrenergic receptor (beta 2AR) into which the putative third cytoplasmic loop of the alpha 1AR had been placed activated phosphatidylinositol metabolism as effectively as the native alpha 1AR, as did a truncated alpha 1AR lacking the last 47 residues in its cytoplasmic tail. Substitutions of beta 2AR amino acid sequence in the intermediate portions of the third cytoplasmic loop of the alpha 1AR or at the N-terminal portion of the cytoplasmic tail caused marked decreases in receptor coupling to phospholipase C. Conservative substitutions of two residues in the C terminus of the third cytoplasmic loop (Ala293----Leu, Lys290----His) increased the potency of agonists for stimulating phosphatidylinositol metabolism by up to 2 orders of magnitude. These data indicate (i) that the regions of the alpha 1AR that determine coupling to phosphatidylinositol metabolism are similar to those previously shown to be involved in coupling of beta 2AR to adenylate cyclase stimulation and (ii) that point mutations of a G-protein-coupled receptor can cause remarkable increases in sensitivity of biological response.
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PMID:Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. 215 97


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