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)

Platelet-derived growth factor (PDGF), a key mitogen for liver fat-storing cells (FSC), is a dimeric molecule that occurs as homodimers or heterodimers of related polypeptide chains (PDGF-BB, -AB, and -AA). In chronic inflammation of the liver lobule, any of the three dimeric forms of PDGF derived from multiple sources could potentially interact with FSC. We explored the effects of the three different PDGF isoforms on DNA synthesis and early signal transduction pathways potentially related to PDGF mitogenicity in rat liver FSC. PDGF-BB homodimer and -AB heterodimer induced a marked increase in DNA synthesis, whereas the effect of PDGF-AA homodimer was considerably lower. Moreover, the mitogenicity of each isoform proportionally correlated with their effects on phosphoinositide turnover and intracellular Ca2+. Both the PDGF-BB and -AB dimers likely interact with the PDGF-beta-receptor, although PDGF-AB requires at least one alpha-receptor. The low responsiveness to PDGF-AA could not be accounted for by downregulation of the PDGF-alpha-receptor because FSC expressed very low levels of PDGF-A- and B-chain mRNAs and did not secrete detectable amounts of PDGF activity in the conditioned media. In addition, preincubation of FSC with suramin, a potent inhibitor of PDGF binding to its receptor, failed to increase PDGF-AA-induced DNA synthesis. These results are consistent with a predominant expression of PDGF-beta-receptor in liver FSC, that is linked to phospholipase C activation.
 ...
PMID:Mitogenic signals for platelet-derived growth factor isoforms in liver fat-storing cells. 200 75

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.
 ...
PMID:Endothelin stimulates PDGF secretion in cultured human mesangial cells. 207 61

Optical methods have recently become available for continuously imaging the free concentrations of important ions and second messengers such as calcium, sodium and hydrogen inside living cells. These ion levels are found to undergo remarkable changes upon stimulation of quiescent cells with growth factors known to stimulate phosphoinositide breakdown. In serum-starved REF-52 fibroblasts, growth factors such as serum, vasopressin, or PDGF (platelet-derived growth factor) cause intracellular [Na+] to increase from about 4 mM to 8 mM. If mitogen treatment is combined with pharmacological depolarization of the membrane potential, repetitive [Ca2+]i spikes result in these rat fibroblasts. The mechanism of this oscillation has been investigated by light-flash release of intracellular messengers such as inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), Ca2+, and diacylglycerol, as well as more traditional biochemical techniques. The key feedback pathway appears to be Ca2(+)-stimulation of phospholipase C production of Ins(1,4,5)P3.
 ...
PMID:Imaging and manipulation of cytosolic ions and messengers during cell activation. 208 12

Recent evidence suggests the involvement of phosphatidylcholine (PC) hydrolysis both in the control of normal cell growth and in transformation. We show here that the simple exogenous addition of Bacillus cereus PC-hydrolyzing phospholipase C (PC-PLC) is sufficient to elicit a potent mitogenic response in Swiss 3T3 fibroblasts by a mechanism that is independent of protein kinase C. Our results on the additivity and synergism between B. cereus PC-PLC, PDGF, and insulin in the mitogenic response indicate that this novel phospholipid degradative pathway may be important in the mitogenic signaling cascade activated by PDGF.
 ...
PMID:Phospholipase C-mediated hydrolysis of phosphatidylcholine is an important step in PDGF-stimulated DNA synthesis. 211 26

The receptors involved in the regulation of phospholipase C by hormones, neurotransmitters and other ligands have seven transmembrane-spanning hydrophobic regions (seven-helix motif) and no known enzymatic activity. Furthermore these receptors can be isolated as complexes with guanine nucleotide binding (G) proteins. Guanine nucleotides affect the binding of hormones that stimulate phospholipase C and it has been possible to see activation of GTPase activity in membranes upon addition of these ligands. Further indirect evidence for a Gp (p stands for phospholipase C activation) protein is the finding that in membranes agonist activation of phospholipase C requires the presence of GTP gamma S a non-hydrolyzable analog of GTP. Furthermore, fluoride is able to activate phospholipase C but its inhibition of phosphatidylinositol-4' kinase (PI-4' kinase) can interfere with efforts to demonstrate this in intact cells. There are four major isozymes of phospholipase C that have been cloned and sequenced. Recently it was found that phospholipase C-gamma as well as PI-3'-kinase are substrates for phosphorylation on tyrosine residues by the EGF and PDGF receptors. The PI-3' kinase is able to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) but the function of this lipid is unknown since it is not a substrate for any known phospholipase C. While much has been learned about the structure and regulation of the phosphoinositide specific kinases and phosphodiesterase enzymes this is a relatively new field in which we can expect many advances during the next few years.
 ...
PMID:Regulation of phosphoinositide-specific phospholipase C. 216 88

Increases in cell phosphatidic acid content occur in response to a wide variety of agonists, many of which have growth promoting properties. These changes have correlated with calcium flux, enzyme activation, gene induction, or cell proliferation. In the current studies we show that exogenous phosphatidic acid (PA) and phosphatidylserine stimulate phosphoinositide hydrolysis and DNA synthesis in cultured human renal mesangial cells. These phospholipids also induce mRNAs for platelet-derived growth factor (PDGF). The activation of phospholipase C by PA appears to be desensitized via protein kinase C as brief preincubation with phorbol ester abrogates the effect. PA-induced DNA synthesis is only partly mediated via protein kinase C as co-incubation with the inhibitor staurosporine blunts DNA synthesis by only one-third. In contrast, induction of PDGF A-chain mRNA is almost totally inhibited by staurosporine. We propose that changes in endogenous phospholipids such as PA or phosphatidylserine may serve as common signaling pathway for a variety of growth factors. Induction of PDGF proto-oncogenes via protein kinase C may represent one mechanism by which this cell activation occurs.
 ...
PMID:Phosphatidic acid modulates DNA synthesis, phospholipase C, and platelet-derived growth factor mRNAs in cultured mesangial cells. Role of protein kinase C. 216 17

Porcine PDGF was found to increase [3H]inositol trisphosphate, [3H]thymidine incorporation and 32P-labelling of polyphosphoinositides in C3H/10T1/2 Cl 8 fibroblasts. These responses to PDGF stimulation were all inhibited by 5 mM neomycin, a polycationic aminoglycoside formerly known to inhibit polyphosphoinositide turnover. PDGF also markedly increased the cellular uptake of inorganic [32P]Pi. This response of PDGF was not inhibited by neomycin (5 mM). Thus, neomycin inhibited PDGF-induced IP3 formation, 32P-labelling of polyphosphoinositides and DNA synthesis, but not cellular uptake of inorganic phosphate. These effects of neomycin suggest a bifurcation of the initial part of the PDGF-induced signal transduction, separating at the receptor level or before phospholipase C activation.
 ...
PMID:Neomycin inhibits PDGF-induced IP3 formation and DNA synthesis but not PDGF-stimulated uptake of inorganic phosphate in C3H/10T1/2 fibroblasts. 216 9

Ligand stimulation of the platelet-derived growth factor receptor (PDGF-R) results in rapid activation of the receptor tyrosine kinase, stimulation of phosphoinositide hydrolysis, an increase in intracellular free Ca2+ concentration ([Ca2+]i), and, ultimately, cellular proliferation. In a previous study, we demonstrated that staurosporine, a known inhibitor of protein kinase C, blocked PDGF-induced [Ca2+]i increases in Swiss mouse 3T3 fibroblasts by a mechanism that appeared unrelated to inhibition of protein kinase activity (Olsen, R., Melder, D., Seewald, M., Abraham, R., and Powis, G. (1990) Biochem. Pharmacol. 39, 968-972). In the present study, we report that staurosporine inhibits ligand-dependent PDGF-R tyrosine kinase activation in cell-free receptor preparations and in intact Swiss 3T3 cells. At the same concentrations (10(-8)-10(-6) M), staurosporine suppressed both the tyrosine phosphorylation of phospholipase C activity and the hydrolysis of phosphoinositides induced by PDGF stimulation of intact cells. In contrast, guanine nucleotide-binding protein-dependent phospholipase C activation induced by bradykinin or fluoroaluminate anion was relatively insensitive to staurosporine. A preferential inhibitory effect of staurosporine on signal generation by the PDGF-R was indicated by findings that epidermal growth factor receptor (EGF-R) tyrosine kinase activity and EGF-dependent phospholipase C in A-431 carcinoma cells were approximately 100-fold less sensitive to this drug. These data indicate that submicromolar concentrations of staurosporine inhibit PDGF-dependent phosphoinositide hydrolysis and Ca2+ mobilization through a proximal inhibitory effect on ligand-induced activation of the PDGF-R tyrosine kinase.
 ...
PMID:Preferential inhibition of the platelet-derived growth factor receptor tyrosine kinase by staurosporine. 217 5

Mitogenic effects of agents activating either the protein kinase C (PDGF; phorbol esters) or the insulin-like growth factor 1 (IGF1)-receptor pathway were studied in quiescent chemically transformed mouse fibroblasts (BP-A31), by evaluating the rate of [3H]thymidine incorporation. Each of these pathways alone was found to be sufficient to sustain progression through the entire cell division cycle. The mitogenic activity of phorbol 12-myristate 13-acetate (PMA) but not that of insulin was blocked by staurosporine (an inhibitor of protein kinase C), in support of the notion that protein kinase C activation was required for the PMA-induced cell cycle progression. The mitogenic effects of PMA were potentiated by cycloheximide pretreatment, and they were abolished by 3-isobutyl-1-methyl xanthine (IBMX; a cyclic nucleotide phosphodiesterase inhibitor). PDGF (known to activate the phospholipase C-protein kinase C pathway) also displayed mitogenic activity in the cycloheximide-pretreated BP-A31 cells, and its effects were prevented by IBMX. In contrast, the mitogenic effects of insulin (at concentrations where it activates the IGF1 receptor) or of IGF1 neither were notably influenced by cycloheximide pretreatment nor were inhibited by IBMX (in the presence of IBMX, the onset of S-phase was delayed by several hours). The expression of the c-fos gene was absent at quiescence; its induction by growth factors was not proportional to their mitogenic potency. Thus, c-fos expression was strongly induced by PMA but only weakly by insulin. IBMX was a powerful inducer of c-fos gene expression but caused a decrease in the level of c-myc mRNA.
 ...
PMID:Mitogenic activity of phorbol esters and insulin-like growth factor 1 in chemically transformed mouse fibroblasts BP-A31: independent effects and differential sensitivity to inhibition by 3-isobutyl-1-methyl xanthine. 246 95

This paper has reviewed, in a broad sense, the potential involvement of the oncogenes and their progenitors, the protooncogenes, in signal transduction pathways. The membrane-associated oncogene products appear to be connected with the generation and/or regulation of secondary messengers, particularly those associated with Ca2+/phospholipid-dependent activation of the serine/threonine kinase protein kinase C. Activation of transmembrane receptors, either through binding their native ligand or through point mutations that lead to constitutive expression, results in the expression of their intrinsic tyrosine-specific protein kinases. In PDGF-stimulated cells, this results in the increased turnover of phosphatidylinositols and the subsequent release of IP3 (Habenicht et al., 1981; Berridge et al., 1984). This coincides with activation of a PI kinase activity (Kaplan et al., 1987). Likewise, the fms product, which is the receptor for CSF-1, induces a guanine nucleotide-dependent activation of phospholipase C (Jackowski et al., 1986). Receptor functions are potentially regulated through differential binding of ligands (as proposed with PDGF), through interactions with other receptors, and through the "feedback" regulation mediated by protein kinase C. PDGF stimulation leads to modulation of the EGF receptor through protein kinase C (Bowen-Pope et al., 1983; Collins et al., 1983; Davis and Czech, 1985). Similarly, the neu product becomes phosphorylated on tyrosine residues following treatment of cells with EGF, although the neu protein does not bind EGF itself (King et al., 1988; Stern and Kamps, 1988). The tyrosine kinases of the src family are not receptors themselves, although they may mediate specific receptor-generated signals. The clck product is physically and functionally associated with the T-cell receptors CD4 and CD8, and becomes active upon specific stimulation of cells expressing those markers (Veillette et al., 1988a,b). The precise physiological role of the src family products has not been established, but their kinase activity is intrinsic to that function. The v- and c-src products are hyperphosphorylated during mitosis (Chackalaparampil and Shalloway, 1988), which correlates with periods of reduced cell-to-cell adhesion and communication (Warren and Nelson, 1987; Azarnia et al., 1988). Furthermore, pp60c-src is associated with a PI kinase activity when complexed with MTAg of polyoma virus, suggesting a function in stimulating increased turnover of the phosphatidylinositols (Heber and Courtneidge, 1987; Kaplan et al., 1987).(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Oncogenes, protooncogenes, and signal transduction: toward a unified theory? 269 May 95


<< Previous 1 2 3 4 5 6 7 8 Next >>