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)

Protein kinase C is a ubiquitous and important regulatory enzyme. The enzyme is physiologically activated in a temporary manner by (S)-diacylglycerols (DAGs), which are themselves generated by the phospholipase C mediated hydrolysis of polyphosphoinositides. The (S)-DAGs specifically bind to the regulatory domain of PKC and cause the activation of the PKC toward substrate. Minor modifications in the DAG result in inactive molecules. On the other hand, the structurally diverse, polycyclic tumor promoters also specifically activate PKC by binding to the same effector site as do the DAGs. The object of this paper is to present a discrete structural model that accounts for the activation of PKC by both the tumor promoters and the DAGs. The unique model presented is based on experimentation rather than on computer-driven hypotheses which, experience has shown, generally produce incorrect structural models when applied to PKC. The model described here begins with a structural analysis of the tumor-promoting debromoaplysiatoxins (DATs). DAT is an ideal starting molecule, because it is conformationally rigid with a known relative and absolute configuration, and it is synthetically manipulable. The pharmacophore of DAT was experimentally determined, and this pharmacophore serves as a template for further analyses. This template is used to predict the active conformer of the acylic DAGs; this conformer is then used to reveal the pharmacophore of various families of tumor promoters. The overall model presented is consistent with published structure-activity studies on the tumor promoters and makes testable predictions that have proven to be correct thus far.
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PMID:Structural basis of protein kinase C activation by diacylglycerols and tumor promoters. 154 May 76

The metabolism of phosphatidylinositol was studied in normal quiescent hepatocytes, hepatocellular carcinomas induced by single dose of diethylnitrosamine, followed by 2-acetylaminofluorene and partial hepatectomy (Solt-Farber model), and in an established hepatoma cell line, JB1. The JB1 hepatoma cell line and hepatocellular carcinomas demonstrated a 4- to 5-fold higher rate of turnover of [3H]-inositol and [3H]-glycerol than the control hepatocytes. Significantly, elevated levels of second messengers inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol were noted in hepatic tumor cells within 4 hr of labeling with precursor molecules, whereas no detectable level of 3H-labeled inositol trisphosphate was noted in quiescent hepatocytes, even after incubation with 10 mM LiCl for 30 min. Approximately 2.5-fold higher specific activities of a guanine nucleotide and Ca+2 dependent phosphatidylinositol 4,5-bisphosphate specific phospholipase C were detected in the hepatocellular carcinoma cells. The cellular location of the phospholipase C activity was also different, being membrane bound in hepatocytes and equally distributed between cytosolic and membrane factions in the hepatomas. These data are consistent with the hypothesis that the enhanced production of diacylglycerol and inositol 1,4,5-trisphosphate in hepatocellular carcinomas may be due to the activation of a guanine nucleotide dependent phosphatidylinositol 4,5-bisphosphate specific phospholipase C. These data are the first to compare phosphoinositide turnover in normal liver and hepatic tumor cells and suggest that the sustained levels of second messengers is closely associated with the transformation and enhanced growth rate in hepatic tumor cells.
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PMID:Altered levels of phosphoinositide metabolites and activation of guanine-nucleotide dependent phospholipase C in rat hepatic tumors. 164 43

Stimulation of phagocytic cells with micromolar concentrations of extracellular ATP primes the production of toxic oxygen metabolites in response to chemoattractants and independently activates a secretory response in vitro. It is hypothesized that extracellular ATP derived from platelet storage granules and damaged endothelium at sites of localized tissue damage or infection may potentiate the pro-inflammatory effects of phagocytic cells in vivo. ATP-dependent functional responses in the phagocyte appear to be due to stimulation of putative P2 purinoreceptors that are coupled to the activation of a phospholipase C via a pertussis toxin-sensitive G-protein. The existence in nature of at least four subtypes of P2 purinoreceptors has been proposed based on the rank order of potency of nucleotide analogs of ATP studied in a variety of cell types. However, no studies involving the structural identification and characterization of the putative receptors have been reported. We have used the Xenopus oocyte expression system to demonstrate acquired adenosine 5'-(thio) triphosphate (ATP gamma S) responsiveness in oocytes injected with mRNA from the promyelocytic leukemia cell line HL60 by measuring the accelerated efflux of intracellular calcium. Two peaks of ATP gamma S responsiveness (Peak I and Peak II) were detected in sucrose gradient fractionated RNA that corresponded to transcript sizes of 4 and 6 kilobases and that were distinct from a third peak previously shown to be enriched in formyl peptide chemoattractant receptor activity. Peak I and Peak II RNA endowed receptor activity in the oocyte that was pharmacologically indistinguishable: ADP and AMP were inactive whereas UTP and ITP exhibited activity that was similar in potency to that of ATP gamma S. Both Peak I and Peak II ATP gamma S-dependent activity was inhibited by pertussis toxin. These data strongly support the concept of phagocytic cell receptors for extracellular nucleotide triphosphates whose ligand specificity is distinct from all other previously described P2 purinoreceptor subtypes, with the exception of the P2 receptor described in Ehrlich ascites tumor cells, by virtue of the ineffectiveness of ADP as a stimulus. These receptors are most likely composed of a single polypeptide chain that can be expressed in the Xenopus oocyte in a functional form regulated by a pertussis toxin-sensitive G-protein.
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PMID:Characterization of phagocyte P2 nucleotide receptors expressed in Xenopus oocytes. 169 46

Thapsigargin (TG), a sesquiterpene lactone and non-phorbol 12-myristate 13-acetate tumor promoter, stimulates a rapid increase in intracellular free Ca2+ [( Ca2+]i) in human T lymphocytes clone P28. The [Ca2+]i response to TG is sustained in the presence of 1 mM extracellular Ca2+, while it becomes transient in Ca2(+)-free medium suggesting that TG activates both the release of Ca2+ from intracellular stores and the entry of Ca2+ from extracellular spaces. TG-induced Ca2+ influx is completely abolished after cell depolarization caused by increased extracellular concentrations of K+. The rise in [Ca2+]i stimulated by TG occurs in the absence of detectable production of inositol phosphates. Moreover, TG does not alter the early biochemical events of T cell activation triggered through the CD2 or the CD3 T cell antigens. Indeed, both inositol phosphate production and intracellular pH increase induced by specific monoclonal antibodies (mAb) remain unchanged after TG treatment. These data suggest that in human T lymphocytes TG releases Ca2+ from an intracellular pool by a mechanism which is independent of the phospholipase C metabolic pathway. Preincubation with TG of T cell clone P28 empties both the CD2 and the CD3-sensitive intracellular Ca2+ pool(s). Conversely, prestimulation of T cell clone P28 by CD3 or CD2-specific mAb inhibits the Ca2(+)-mobilizing effect of TG. Thus it appears that TG and CD2- or CD3-specific mAb mobilize Ca2+ from common Ca2+ pool(s). Taken together, these results demonstrate that Ca2+ influx in human T cells may be linked to mobilization of intracellular Ca2+ pools and by a mechanism independent of phosphoinositide hydrolysis. They further indicate that the release of intracellular Ca2+ pool(s) may play a major role in the opening of cell membrane Ca2+ channels observed during the CD2- or CD3-induced stimulation of human T lymphocytes.
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PMID:Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin. 170 Jul 52

Phosphatidylinositol-specific phospholipase C (PI-PLC) is an enzyme that has the capacity to release glycosyl-phosphatidyl inositol (G-PI)-anchored proteins from the cells surface. Pretreatment of the human T-cell leukemia cell line Molt-4 with PI-PLC resulted in a decrease in the susceptibility to lysis by natural killer (NK) cells. Treatment of the erythroleukemia cell line K562 with PI-PLC had no effect on its NK susceptibility. PI-PLC-treated and untreated Molt-4 bound equally well to lymphocytes in target-binding studies with effector cell preparations enriched for NK cells. Susceptibility to cytolytic granules isolated from rat LGL tumor cells remained the same after treatment of Molt-4 or K562 with PI-PLC. Combined treatment of Molt-4 with PI-PLC and rlFN-alpha or rlFN-gamma resulted in additive reductions of the NK susceptibility, suggesting that PI-PLC and interferons act on different mechanisms to protect cells from NK lysis. When expression of a number of antigens on Molt-4 and K562 was analyzed in flow cytometry, only the expression of CD58 was reduced after PI-PLC treatment. The susceptibility of Con A blasts to MLR derived cytotoxic T-cells was not altered by treatment with phospholipase. These data suggest that PI-PLC treatment reduces the capacity of some target cells to activate NK cells upon contract. The mechanism behind this phenomenon is presently unclear.
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PMID:Phospholipase C treatment of certain human target cells reduces their susceptibility to NK lysis without affecting binding or sensitivity to lytic granules. 170 25

Changes in the expression of several genes play critical roles in cell growth and tumor transformation. A number of proteases are increased in some tumors, and the level of these enzymes correlates with the metastatic potential of several cancer cell lines. Stromelysin, with the widest substrate specificity, can degrade the extracellular matrix conferring metastatic potential to tumor cells. The mechanisms whereby growth factors and oncogenes control the expression of stromelysin are beginning to be characterized. In the study shown here we also identify a region in the stromelysin promoter which is involved in the induction of stromelysin in response to platelet-derived growth factor, phosphatidylcholine-hydrolyzing phospholipase C, and ras oncogene. Our results are consistent with the notion that platelet-derived growth factor/phosphatidylcholine-hydrolyzing phospholipase C induces stromelysin gene expression through a phorbol myristate acetate/protein kinase C-independent mechanism by acting through elements in the stromelysin promoter distinct from the 12-O-tetradecanoylphorbol-13-acetate-responsive element.
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PMID:Protein kinase C-independent expression of stromelysin by platelet-derived growth factor, ras oncogene, and phosphatidylcholine-hydrolyzing phospholipase C. 171 97

Immunological and biochemical characteristics of the Qa-2 murine nonclassical histocompatibility class 1 antigen expressed on tumor cells derived from H-2k (Qa-2-) mice were studied. It was found that the Qa-2 antigen on normal H-2b lymphocytes reacted with Qa-2-specific monoclonal antibodies (mAbs) 34-1.2, 59 (both specific to the alpha 1/alpha 2 region) and 141-15.8 (specific to the alpha 3 domain), and the Qa-2 antigen on H-2k tumor cells (Qa-2k antigen) reacted with mAbs 59 and 141-15.8, but not with 34-1.2. The normal Qa-2 antigen was susceptible to treatment with phosphatidylinositol-specific phospholipase C, but the Qa-2k antigen was insensitive to it. By Northern hybridization, polymerase chain reaction (PCR) studies on cDNA, Southern hybridization, Western blotting, and nucleotide sequence analysis, the Q5k gene was identified as the gene encoding the Qa-2k antigen expressed on BW5147 lymphoma cells derived from a mouse of AKR strain (H-2k, Qa-2-). The nucleotide sequence of PCR-amplified BW5147 Q5k cDNA showed complete agreement with the reported sequence of exons 1-5 of the Q5k gene of C3H/He. It also showed complete deletion of the region corresponding to exons 6 and 7, and a very short coding region in exon 8, resulting in very short cytoplasmic domain of the product compared with regular class 1 antigens. These characteristics were expected from the reported Q5k genomic sequence. These results revealed that the Qa-2k antigen was distinct from the normal Qa-2 antigen expressed on H-2b lymphocytes although it cross-reacted with some Qa-2-specific mAbs.
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PMID:Expression of the Qa-2k phenotype encoded by the Q5k gene on the surface of tumor cells derived from H-2k mice. 174 Jun 59

Three Carcinoembryonic Antigen (CEA) gene family members: CEA, Non-specific cross-reactive antigen 50/90 (NCA) and biliary glycoprotein (BGP) were expressed in the colon carcinoma cell lines LS174T and HT29. The CEA, NCA50/90 and four alternatively spliced BGP transcripts (BGP a-d) were identified. The molecular weights of the mature glycoproteins were: CEA, 180kD; NCA50/90, 70-100 kD; BGP, 85, 120 and 140 kD. Pulse chase experiments demonstrated that CEA first appears as a 165 kD high mannose precursor which is trimmed to a 160 kD intermediate and finally transformed into the mature 180 kD glycoprotein. The precursor form of NCA had a molecular weight of 50 kD. CEA and NCA50/90, but not BGP, were linked to the cell membrane via glycosyl phosphatidyl inositol and could be released from the intact tumor cells by glycosyl phosphatidyl inositol-specific phospholipase C. CEA on isolated membranes and in cell lysates, but not on intact cells, was also cleaved by fresh human serum or purified glycosyl phosphatidyl inositol-specific phospholipase D.
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PMID:Biosynthesis of carcinoembryonic antigen (CEA) gene family members expressed in human tumor cell lines: evidence for cleavage of the glycosyl phosphatidyl inositol (GPI) anchor by GPI-PLC and GPI-PLD. 181 6

Tumor-promoting phorbol esters, e.g., 12-O-tetradecanoylphorbol 13-acetate (TPA), inhibit TSH-stimulated iodide organification in vitro implying a role for protein kinase C (PKC) in the regulation of differentiated thyroid function. To further explore the PKC dependence of this action of TPA, we studied the effects of PKC inhibition and downregulation on phorbol-mediated differentiated thyroid function in vitro. In addition, the effects of the nonphorbol PKC activator, phospholipase C (PLC) were studied. TPA (100 nM) inhibited TSH-stimulated iodide organification in cultured porcine thyroid cells by over 95% and caused PKC translocation in vitro. Exogenous PLC (1 U/mL) could mimic these effects of TPA. The PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) inhibited TSH-stimulated iodide organification at concentrations exceeding 10 microM. However, partial recovery of phorbol- and PLC-inhibited iodide organification was seen in the presence of identical concentrations of H7. H7 had no effect on PKC translocation in porcine thyroid cell extracts. After 24 h of TPA treatment to induce PKC downregulation, no recovery of TSH-stimulated iodide organification was observed, suggesting that the effects of TPA were irreversible. These studies indicate that the effects of TPA and PLC on differentiated thyroid function are mediated, at least in part, by PKC. These findings provide further evidence for a role for PKC in the regulation of differentiated thyroid function.
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PMID:Phorbol ester and phospholipase C-mediated differentiated thyroid function in vitro: the effects of protein kinase C inhibition and downregulation. 182 67

We have recently generated a series of gamma/delta T cell clones able to kill, after in vitro immunization, an Epstein-Barr Virus-transformed B cell line (designated E418) in a non-major histocompatibility complex-requiring fashion. A monoclonal antibody, termed anti-10H3, produced against E418 was selected by its ability to block these cytotoxic interactions. Further analysis indicated that the inhibitory effects of anti-10H3 were highly selective (i.e., no blocking activity with multiple control clones used as effector cells; no alteration of the natural killer-like function mediated by the relevant gamma/delta clones against 10H3+ tumor cells such as Rex). The molecule immunoprecipitated by anti-10H3, termed TCT.1, was characterized as a 43-kD protein broadly distributed in the hematopoietic system. The TCT.1 molecule has been further studied here by protein microsequencing. Results show that the TCT.1-derived peptide sequences are virtually identical to corresponding regions of Blast-1, a previously described surface protein with unknown function. The likely identity of the two molecules has been strengthened by analyzing the susceptibility of TCT.1 to phosphatidylinositol-specific phospholipase C digestion in light of the known anchorage of Blast-1 to the cell membrane through a glycosyl-phosphatidylinositol-containing lipid. The TCT.1/Blast-1-encoding gene is well characterized; it belongs to the immunoglobulin gene superfamily and it is located in the same band of chromosome 1 as the CD1 gene cluster. Together, these data further support the view that proteins distinct from the conventional class I/II histocompatibility molecules are involved in specific T cell recognition.
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PMID:TCT.1, a target molecule for gamma/delta T cells, is encoded by an immunoglobulin superfamily gene (Blast-1) located in the CD1 region of human chromosome 1. 182 26


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