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)

The studies described above have led to some conclusions as well as some speculations regarding the participation of oncogenes in proliferation. It is important to make a clear distinction between the data described along with the resulting conclusions, and the highly speculative models which have been proposed here to describe these results. On the basis of the results described, several conclusions appear to be indicated. First, it is clear that in normal cells of many types ras proteins are required for proliferation. Second, these proteins are needed for the maintenance of the transformed phenotype induced by some, but not all, oncogenes. Third, the activity of ras proteins is not apparently involved in controlling the activity of phospholipase C or any other identifiable phospholipase. Finally, tumor formation appears to involve the development of a proliferative phenotype which functions independently of ras activity. To explain these data, a model of proliferative control is presented. This model is highly speculative at this time and is based upon the assumption that the "ras pathway" involves the sequential action of cellular genes related to the retroviral oncogenes. The function of this pathway is to pass the proliferative signal generated by an occupied growth factor receptor into the cell. It is clearly needed late in the G-1 phase of the cell cycle, but the "ras pathway" might also be involved in the early events associated with mitogenic stimulation. Due to its central role in the control of proliferation and the fact that tumor cells circumvent its action, ras proteins are postulated to a site of negative proliferative control. After the action of ras and related cellular oncogenes, the proliferative control signal no longer involves the action of a simple linear sequence of protein activities, but might involve multiple, interdependent pathways. This model is primarily of value as a working hypothesis and does not account for many observations central to proliferative control such as the involvement of cell-cell contact, differentiation, and the action of factors which inhibit rather than promote proliferation, such as interferons. The model does summarize the data described and even in the simplest form represents a novel approach to explain proliferative control in terms of the activities of known genes.
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PMID:The ras pathway: a model for the control of proliferation in animal cells. 306 84

Data indicating that the 21-kDa protein (p21) Harvey-ras gene product shares sequence homology with guanine nucleotide-binding proteins (G proteins) has stimulated research on the influence(s) of p21 on G-protein-regulated systems in vertebrate cells. Our previous work demonstrated that NIH-3T3 mouse cells expressing high levels of the cellular ras oncogene isolated from the EJ human bladder carcinoma (EJ-ras) exhibited reduced hormone-stimulated adenylate cyclase activity. We now report that in these cells another enzyme system thought to be regulated by G proteins is inhibited, namely phospholipases A2 and C. NIH-3T3 cells incubated in plasma-derived serum release significant levels of prostaglandin E2 (PGE2) as determined by radioimmunoassay when exposed to platelet-derived growth factor (PDGF) at 2 units/ml; the levels of PGE2 released from EJ-ras-transfected cells are only 3% those of controls despite a similar basal (unstimulated) release from control and EJ-ras-transfected cells. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells is not due to a defect in the prostaglandin cyclooxygenase enzyme, since incubation of control cells and EJ-ras-transfected cells in 0.33, 3.3, or 33 microM arachidonate resulted in identical levels of PGE2 release. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells also does not result from the loss of functional PDGF receptors. EJ-ras-transformed cells bind 70% as much 125I-labeled PDGF as control cells and are stimulated to incorporate [3H]thymidine and to proliferate after exposure to PDGF. Moreover, this inhibition is not likely the result of a secondary cellular effect related to the transformed phenotype, since NIH-3T3 cells transformed by v-src released PGE2 at wild-type levels after exposure to PDGF. Determination of total water-soluble inositolphospholipids and changes in the specific activities of phosphatidylcholine in control and EJ-ras-transfected cells demonstrated that PDGF-stimulated phospholipase C and A2 activities are inhibited in the EJ-ras-transfected cells.
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PMID:Loss of platelet-derived growth factor-stimulated phospholipase activity in NIH-3T3 cells expressing the EJ-ras oncogene. 309 98

Our previous work demonstrated that NIH-3T3 cells expressing high levels of the mutated cellular ras oncogene (EJ-ras gene) exhibited reduced hormone-sensitive adenylate cyclase and platelet-derived growth factor-stimulated (PDGF) phospholipase A2/C activities. We now report that although the ras-transformed cells display markedly reduced phospholipase C activity, as measured by the levels of inositol 1,4,5-trisphosphate synthesized after PDGF-stimulation, normal levels of phospholipase A2 activity can be uncovered; thus, similar levels of prostaglandin E2 were synthesized in EJ-ras transformed and control cells after stimulation with phorbol myristate acetate (PMA) and/or the calcium ionophore A-23187, agents which stimulate protein kinase C and intracellular Ca2+ levels, respectively. These data suggest that the EJ-ras gene product uncouples the PDGF receptor from the phospholipase C, resulting in reduced PDGF-stimulated Ca2+ mobilization, protein kinase C stimulation and an apparent decrease in Ca2+-dependent phospholipase A2.
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PMID:The lack of PDGE-stimulated PGE2 release from ras-transformed NIH-3T3 cells results from reduced phospholipase C but not phospholipase A2 activity. 311 66

Platelet-derived growth factor (PDGF), the calcium ionophore A23187, and the tumor promoter phorbol myristate acetate stimulated c-fos mRNA levels in control NIH 3T3 cells. However, NIH 3T3 cells transformed by EJ-ras DNA transfection, which have diminished PDGF-stimulated phospholipase C activity, showed a 95% reduction in PDGF-stimulated c-fos mRNA levels. The responses to A23187 and phorbol myristate acetate were also attenuated, but not as severely as the PDGF-mediated induction. The reduction in PDGF-stimulated c-fos induction did not appear to be a general result of cellular transformation, since src-transformed NIH 3T3 cells displayed a strong PDGF-stimulated c-fos induction. Despite the reduction in PDGF-stimulated c-fos induction, EJ-ras-transformed cells still responded mitogenically to PDGF. These data suggest that the magnitude of c-fos induction cannot be directly correlated with PDGF-stimulated mitogenesis in EJ-ras-transformed NIH 3T3 cells.
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PMID:Platelet-derived growth factor does not induce c-fos in NIH 3T3 cells expressing the EJ-ras oncogene. 314 5

Cellular ras activity has been neutralized in 3T3 cells by microinjection of a specific anti-ras monoclonal antibody. The injected antibody efficiently inhibited proliferation in cells treated with a phorbol ester and a calcium ionophore, or with prostaglandin F2 alpha. These treatments were designed to imitate the action of phospholipase C or of phospholipase A2. In addition, the highly efficient mitogenic potential of phosphatidic acid was inhibited by the injected antibody even more efficiently than was serum-induced proliferation. The close reliance of phospholipid-induced mitogenesis upon ras activity suggests that ras proteins are unlikely to function to control the action of a phospholipase.
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PMID:Cellular ras activity and phospholipid metabolism. 327 10

The role of ras proteins in signal transduction was assessed by studying inositol phospholipid metabolism and inositol phospholipid-mediated cellular responsiveness to agonists in cells transformed by ras and other oncogenes. Specific alterations were observed in the inositol phospholipid cycle of ras-transformed fibroblasts, but similar changes were also produced by spontaneous transformation or transformation mediated by either membrane-associated oncogenes, such as src, met, or trk, or cytoplasmic oncogenes, mos and raf; the nuclear oncogenes fos and myc did not produce these changes. The alterations included (i) stimulation of phospholipase A2 activity as indicated by elevated levels of glycerophosphoinositol and nonesterified arachidonic acid and (ii) specific uncoupling between surface receptor-mediated stimulation by platelet-derived growth factor, bombesin, or serum and activation of intracellular phospholipase C. These findings suggest the existence of common biochemical pathways for transformation by cytoplasmic and membrane-associated oncogenes and are not consistent with the hypothesis that 21-kDa ras proteins (p21) are direct or distinct regulatory elements of phospholipase C or phospholipase A2 in inositol phospholipid signal transduction pathways.
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PMID:Malignant transformation by ras and other oncogenes produces common alterations in inositol phospholipid signaling pathways. 328 89

NIH-3T3 cells transformed by the EJ-ras oncogene synthesize only 10-15% as much inositol 1,4,5-trisphosphate (InsP3) as control cells after stimulation with platelet-derived growth factor (PDGF). This is despite the fact that the basal (unstimulated) levels of InsP3 synthesized in control and EJ-ras-transformed cells are not significantly different. Using the fluorescent indicator fura-2 and digital-imaging techniques, we have visualized and quantified changes in intracellular Ca2+ concentrations in control and EJ-ras-transformed NIH-3T3 cells in response to PDGF. Within 3 min after exposure of control cells to PDGF, intracellular Ca2+ levels are increased 3- to 9-fold, paralleling the increase in InsP3. In contrast, the majority (greater than 90%) of the EJ-ras-transformed cells show no increase in Ca2+ levels after PDGF exposure and the few that did respond exhibited only a small transient increase. Pronounced differences in the intracellular localization of Ca2+ increases in control and the responding EJ-ras-transformed cells were also observed. Despite the inhibition of InsP3 synthesis and subsequent Ca2+ mobilization, the EJ-ras-transformed cells respond mitogenically to PDGF. These data do not support the hypothesis that the EJ-ras gene product (p21) stimulates a phosphatidylinositol 4,5-bisphosphate-specific phospholipase C in NIH-3T3 cells; instead they suggest that the EJ-ras p21 may uncouple the PDGF receptor from phospholipase C resulting in inhibition of PDGF-stimulated activity of phospholipase C, InsP3 synthesis, and Ca2+ mobilization.
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PMID:NIH-3T3 cells transformed by the EJ-ras oncogene exhibit reduced platelet-derived growth factor-mediated Ca2+ mobilization. 328 91

Genes involved in the transduction of signals required for normal cell proliferation commonly appear to be subverted in the neoplastic process. One such group is the highly conserved family of ras genes, which have been detected as transforming genes in a wide variety of naturally occurring tumours. By analogy with other known G proteins, the p21 proteins encoded by ras genes may act as regulatory proteins in the transduction of signals that lead to DNA synthesis. A major pathway involved in the DNA synthesis induced by growth factors is mediated by phosphatidylinositol turnover: cleavage of phosphoinositides by phospholipase C produces 1,2-diacylglycerol, and inositol phosphates. The former acts as an essential cofactor for protein kinase C (ref. 4), and inositol-(1,4,5)-triphosphate mobilizes Ca2+ from non-mitochondrial intracellular stores. We demonstrate a reproducible increase in 1,2-diacylglycerol, in the absence of a detectable increase in inositol phosphates, in transformed cells containing Ha-ras oncogenes and with different membrane targeting signals for the ras p21 protein. These findings suggest that a source other than phosphoinositides exists for the generation of 1,2-diacylglycerol and that the Ha-ras oncogene specifically activates this novel pathway for 1,2-diacylglycerol production.
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PMID:Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. 331 65

Protein kinase C (PKC), a Ca2+-and phospholipid-dependent protein kinase, is now known to be regulated by sn-1,2-diacylglycerol (DAG) second messengers and is the intracellular phorbol ester receptor. Models of transmembrane signaling events that elicit DAG production include receptor-mediated G protein-dependent activation of phospholipase C. Several products of oncogenes resemble transmembrane signaling elements; critical second-messenger levels may, therefore, be altered by genetic defects in these elements. We found that normal rat kidney cells transformed with ras and sis contained elevated levels of DAG, and cells transformed with temperature-sensitive K-ras had elevated DAG levels at the permissive but not the restrictive temperature. To study the mechanism of PKC activation by phosphatidylserine (PS), DAG, and Ca2+, we used mixed micelles of Triton X-100, and analogous methods to examine PS dependence on [3H]phorbol-dibutyrate binding and activation. PKC activation occurs at physiological mole fractions of PS and DAG and does not require a bilayer. Activation by PS, which was cooperative, required four or more molecules. Activation by DAG was not cooperative and one molecule was sufficient. Monomeric PKC is the active species. Our activation model suggests that PKC binds to Ca2+ and four PS carboxyl groups to form a surface-bound, "primed" but inactive complex. DAG binds to the complex of the four PS carboxyl groups, the Ca2+, and the PKC through three bonds, two to ester carbonyls and one to the 3-hydroxyl moiety. Collectively, these may cause a conformational change and activate the enzyme.
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PMID:Mechanism of regulation of protein kinase C by lipid second messengers. 332 5

The receptors for insulin and PDGF are tyrosine kinases that mediate distinct effects in identical cellular backgrounds. Each receptor must therefore engage a unique subset of the available signaling elements--at least partly through the selection of proteins with src-homology 2 domains (SH2 proteins). Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. Association with IRS-1 activated PtdIns 3'-kinase more effectively than association with the PDGFr. Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). Furthermore, IRS-1 binds a different subset of SH2 domain-containing proteins than does the PDGFr and regulates at least one common element (PtdIns 3'-kinase) differently than the PDGFr. These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules.
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PMID:Common and distinct elements in insulin and PDGF signaling. 748 83


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