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)

Mitogens and vasoconstrictors stimulate many of the same early intracellular signals (e.g. phospholipase C and protein kinase C activation) in vascular smooth muscle cells (VSMC). Despite these shared signals, angiotensin II is not mitogenic for cultured VSMC. The nonmitogenic effect of angiotensin II suggests that other intracellular signals associated with growth should differ between mitogens and vasoconstrictors. Because of the importance of intracellular pH (pHi) in growth, we compared the effects of 10% calf serum, 10 ng/ml platelet-derived growth factor, and 100 nM angiotensin II on pHi and Na+/H+ exchange. All agonists stimulated a rapid (less than 1 min) rise in pHi mediated by Na+/H+ exchange. However, exposure of growth-arrested VSMC to these agonists for 24 h caused significant differences in pHi: 7.18 (10% serum), 7.16 (platelet-derived growth factor), 6.99 (angiotensin II), and 7.08 (0.4% serum). Na+/H+ exchange activity was measured in acid-loaded cells by the ethyl isopropyl amiloride-sensitive influx of Na+ and efflux of H+. Both techniques showed that exposure to 10% serum caused approximately 45% decrease in Na+/H+ exchange activity without significant change in angiotensin II-treated cells. Thus, although the rapid changes in pHi and Na+/H+ exchange function are the same for angiotensin II and mitogens, the long term effects differ. The data suggest that differences in pHi regulatory mechanisms are important in determining whether an agonist causes VSMC hypertrophy or hyperplasia.
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PMID:Hypertrophy and hyperplasia cause differing effects on vascular smooth muscle cell Na+/H+ exchange and intracellular pH. 217 46

Calcium has been implicated as a regulatory factor in many physiological and pathophysiological processes in the renal cell. Under physiological conditions, the cytosolic free calcium concentration is maintained at approximately 100 nM. Most of the releasable cell Ca2+ resides in the nonmitochondrial compartments. In addition to the plasma membrane Ca2+ transport processes, there is a high-affinity, low-capacity buffering capability of nonmitochondrial organelles and a lower-affinity high-capacity mitochondrial Ca2+ buffering capability. A critical enzymatic effector of Ca2+ action in the cell is phospholipase A2. By using digitonin-permeabilized renal mesangial cells, the [Ca2+] dependency of phospholipase A2 was characterized. The [Ca2+] sensitivity was insufficient to explain the phospholipase A2 activation observed with vasopressin. In both intact cells, as well as permeabilized cells, it was found that protein kinase C activation markedly enhanced the Ca2+ calmodulin-dependent activation of phospholipase A2. In response to platelet-derived growth factor, it was found that arachidonic acid release preceded phospholipase C activation. This suggests that other effectors besides Ca2+ and protein kinase C may also be important for phospholipase A2 activation. In an experimental model designed to mimic postischemic reperfusion damage to renal mitochondria, it was demonstrated that reactive oxygen species act synergistically with Ca2+ to activate mitochondrial phospholipase A2, which mediates damage to site I of the electron transport chain, the F1F0 ATPase, and the adenine nucleotide translocase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium in renal cells. Modulation of calcium-dependent activation of phospholipase A2. 219 Aug 10

Arachidonate metabolites modulate glomerular mesangial cell contractility through specific receptors coupled to phospholipase C or adenylate cyclase. The resulting intracellular signals, including changes of cytosolic Ca2+, pH, and cyclic adenosine 3'5'-monophosphate (cAMP) are known to also regulate the growth of many cell types. Since eicosanoids have been shown to interfere with cell proliferation in culture, we studied DNA synthesis and cell number in rat mesangial cell cultures exposed to a selective phospholipase C activator, prostaglandin F2 alpha (PGF2 alpha), or to the cAMP-stimulating PGI2 analogue, Iloprost. PGF2 alpha dose-dependently enhanced DNA synthesis and cell proliferation in the presence of insulin, with an EC50 of 0.1 microM. This eicosanoid potentiated the effects of platelet-derived growth factor (PDGF) or low concentrations of serum. Maximum stimulatory potency was about one-third that of PDGF. Removal of PGF2 alpha after short-term stimulation (30 min) did not reverse its mitogenic effect. Iloprost had no effect on DNA synthesis of quiescent cells, but potently inhibited growth stimulated by various concentrations of fetal serum. PG released within the glomerular microcirculation may play a regulatory role in both normal and deranged mesangial cell growth.
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PMID:Prostaglandins and rat glomerular mesangial cell proliferation. 234 24

We compared the mechanisms by which thrombin and platelet-derived growth factor (PDGF) activate phospholipase C in cultured vascular smooth muscle cells. Thrombin caused a transient (less than 5 min) increase in inositol trisphosphate (IP3) while PDGF caused a sustained (greater than 10 min) increase. Both pertussis toxin and phorbol 12-myristate 13-acetate (PMA) inhibited the thrombin-induced increase in IP3 but neither agent affected the PDGF-induced increase in IP3. To examine the role of GTP binding (G) proteins in the activation of phospholipase C by these two hormones, GTP analogues were introduced into saponin-permeabilized cells. In the absence of hormones, guanosine 5'-O-(3-thiotrisphosphate) (GTP gamma S) caused a progressive increase in IP3 release which was inhibited 55% by PMA (200 ng/ml). In the presence of thrombin, GTP gamma S caused synergistic increase in IP3 release. The synergism between GTP gamma S and thrombin was virtually eliminated by 10 min prior exposure to PMA (200 ng/ml). When PDGF was the hormonal agonist, GTP gamma S also caused synergistic increase in IP3 release and guanosine 5'-O-(2-thiodiphosphate) blunted PDGF-induced IP3 release. However, in contrast to thrombin, the synergism between GTP gamma S and PDGF was unaffected by PMA. Thus, thrombin and PDGF activate phospholipase C by signal transduction systems which differ in kinetic properties and in sensitivity to PMA and pertussis toxin. Despite these differences, both systems appear to involve GTP binding proteins at some step.
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PMID:Guanosine 5'-O-(3-thiotrisphosphate) potentiates both thrombin- and platelet-derived growth factor-induced inositol phosphate release in permeabilized vascular smooth muscle cells. Signaling mechanisms distinguished by sensitivity to pertussis toxin and phorbol esters. 249 71

NIH-3T3 cells transformed by the EJ-ras oncogene display reduced platelet-derived growth factor (PDGF)-stimulated phospholipase C activity as measured by inositol 1,4,5-triphosphate (IP3) synthesis and Ca2+ mobilization. The lack of PDGF-stimulated Ca2+ mobilization in EJ-ras transformed cells is not due to a loss of IP3 sensitivity, because microinjected IP3 elevates intracellular Ca2+. Treatment of EJ-ras transformed cells with cholera toxin or 8-bromo-cyclic AMP, but not pertussis toxin or the beta-subunit of cholera toxin, results in a slight recovery of PDGF-stimulated IP3 synthesis, a marked increase in intracellular Ca2+ mobilization, and an almost complete recovery of prostaglandin E2 biosynthesis. These data suggest that EJ p21-mediated inhibition of PDGF-stimulated intracellular events can be partially and transiently reversed by cyclic AMP.
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PMID:Cyclic AMP can partially restore platelet-derived growth factor-stimulated prostaglandin E2 biosynthesis, and calcium mobilization in EJ-ras-transformed NIH-3T3 cells. 254 Nov 40

The effect of scrape-loaded [Val-12]p21ras on agonist-stimulated phosphatidylinositol 4,5-bisphosphate (PIP2) turnover in Swiss-3T3 cells was studied. Previously [Morris, Price, Lloyd, Marshall & Hall (1989) Oncogene 4, 27-31] we demonstrated that [Val-12]p21ras activates protein kinase C within 10 min of scrape loading. Here, we show that [Val-12]p21ras inhibits bombesin and platelet-derived growth factor-stimulated PIP2 breakdown 1.5-4 h after scrape loading. This effect persisted for at least 18 h and could be mimicked in control cells by activation of protein kinase C with 12-O-tetradecanoyl 13-acetate (TPA) 15 min prior to ligand stimulation. When protein kinase C was down-regulated by chronic TPA treatment, [Val-12]p21ras was no longer able to inhibit agonist-stimulated inositol phosphate production. These results indicate that changes in inositol phosphate levels caused by ras protein are probably due to activation of protein kinase C and not to an interaction of ras with phospholipase C.
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PMID:Scrape-loaded p21ras down-regulates agonist-stimulated inositol phosphate production by a mechanism involving protein kinase C. 254 49

We investigated the mechanism(s) whereby activation of a growth-factor receptor typically endowed with tyrosine kinase activity, such as the platelet-derived growth factor (PDGF) receptor, triggers phosphoinositide hydrolysis. In Swiss 3T3 cells permeabilized with streptolysin O, an analogue of GTP, guanosine 5'-[gamma-thio]triphosphate, was found to potentiate the coupling of the bombesin receptor to phospholipase C. In contrast, the activation of the enzyme by PDGF occurred in a GTP-independent manner. Moreover, the inactive analogue of GTP, guanosine 5'-[beta-thio]diphosphate, significantly inhibited the bombesin-induced InsP3 generation, whereas it did not decrease the same effect when stimulated by PDGF.
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PMID:Differential mechanisms of inositol phosphate generation at the receptors for bombesin and platelet-derived growth factor. 255 6

The ability of three pure types of bovine brain phospholipase C (PLC) and one pure rat liver PLC to utilize as substrates the recently discovered phosphatidylinositol 3-phosphate (PI-3-P), a putative phosphatidylinositol 3,4-bisphosphate (PI-3,4-P2), and phosphatidylinositol trisphosphate (PIP3) was investigated. PI-3-P, PI-3,4-P2, and PIP3 are the products of phosphorylation of PI, PI-4-P, and PI-4,5-P2, respectively, by phosphoinositide 3-kinase activities that are associated with certain protein-tyrosine kinases. Although these new phospholipids have been found in intact cells, PI-3,4-P2 and PIP3 appear only after stimulation of quiescent cells with growth factors such as platelet-derived growth factor (Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P., and Cantley, L. C. (1989) Cell 57, 167-175) and after transformation by certain oncoproteins (L. A. Serunian, K. R. Auger, T. M. Roberts, and L. C. Cantley, manuscript in preparation). Mixtures of [3H]PI-4-P plus [32P]PI-3-P or [3H]PI-4,5-P2 plus [32P]PI-3,4-P2 or PIP3 alone were used as substrates for PLCs in vitro. After incubation with enzyme followed by extraction with chloroform/methanol/HCl, the ratio of 3H/32P in the aqueous layer revealed the selective hydrolysis of PI-4-P and PI-4,5-P2 over PI-3-P and PI-3,4-P2. High performance liquid chromatography analysis of the aqueous layer containing reaction products confirmed that only PI-4-P and PI-4,5-P2, were hydrolyzed to inositol 1,4-P2 and inositol 1,4,5-P3, respectively. These findings suggest that the turnover of PI-3-P, PI-3,4-P2, and PIP3 occurs independently of the turnover of PI-4-P and PI-4,5-P2.
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PMID:Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipases C from rat liver and bovine brain. 255 93

Quiescent mouse NIH3T3 cells expressing a transduced human c-fms gene encoding the receptor for colony stimulating factor-1 (CSF-1) were stimulated with mitogenic concentrations of platelet-derived growth factor (PDGF) or CSF-1. Immunoprecipitated phospholipase C-gamma (PLC-gamma) was phosphorylated on tyrosine and calcium was mobilized following treatment of intact cells with PDGF. In contrast, only trace amounts of phosphotyrosine were incorporated into PLC-gamma and no intracellular calcium signal was detected after CSF-1 stimulation. Similarly, CSF-1 treatment did not stimulate phosphorylation of PLC-gamma on tyrosine in a CSF-1-dependent. SV40-immortalized mouse macrophage cell line that expresses high levels of the CSF-1 receptor. In fibroblasts, antiserum to PLC-gamma co-precipitated a fraction of the tyrosine phosphorylated form of the PDGF receptor (PDGF-R) after ligand stimulation, implying that phosphorylated PDGF-R and PLC-gamma were associated in a stable complex. Pre-treatment of cells with orthovanadate also led to tyrosine phosphorylation of PLC-gamma which was significantly enhanced by PDGF, but not by CSF-1. Thus, although the PDGF and CSF-1 receptors are structurally related and appear to be derived from a single ancestor gene, only PDGF-induced mitogenesis in fibroblasts correlated with tyrosine phosphorylation of PLC-gamma.
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PMID:Phospholipase C-gamma, a substrate for PDGF receptor kinase, is not phosphorylated on tyrosine during the mitogenic response to CSF-1. 255 62

Phosphatidylinositol 3-phosphate (PtdIns(3)P), a recently described phospholipid, has been linked to polyoma virus-induced cellular transformation and platelet-derived growth factor-mediated mitogenesis. PtdIns(3)P, in contrast to phosphatidylinositol, phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), is resistant to hydrolysis by bovine brain phospholipase C gamma. We present here the identification of a phosphomonoesterase activity from the soluble fraction of NIH 3T3 cells which removes the phosphate from the D-3 position of PtdIns(3)P. This enzyme is specific as it has little or no activity on the monoester phosphates of PtdIns(4)P, PtdIns(4,5)P2, or inositol 1,3-bisphosphate and is tentatively designated phosphatidylinositol 3-phosphatase (PtdIns 3-phosphatase). The enzyme does not require added metal ions for activity and is maximally active in the presence of EDTA. It is inhibited by Ca2+, Mg2+, Zn2+, and the phosphatase inhibitor VO4(3-). In addition, there is no phospholipase C activity toward PtdIns(3)P in the soluble fraction of NIH 3T3 cells. In view of the absence of a phospholipase C activity that hydrolyzes PtdIns(3)P, we propose that PtdIns(3)P is not a precursor for a soluble inositol phosphate messenger but that it instead may act directly to control certain cellular processes or as a precursor for other phosphatidylinositols. PtdIns 3-phosphatase may thus terminate a metabolic signal or regulate precursor levels for other phosphatidylinositols that are phosphorylated in the D-3 position.
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PMID:The discovery of a 3-phosphomonoesterase that hydrolyzes phosphatidylinositol 3-phosphate in NIH 3T3 cells. 255 36


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