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 findings reported herein indicate that insulin rapidly perturbs phospholipid metabolism and consequent intracellular signalling, in its target tissues by two fully separable mechanisms. One of these mechanisms involves a pertussis toxin-sensitive Gi alpha, which probably serves to couple the insulin receptor to a PI-glycan phospholipase C, which, in turn, leads to the release of HGM and consequent activation of de novo PA synthesis. The second mechanism is PC hydrolysis, which is pertussis toxin-insensitive. Both mechanisms serve as important sources of DAG during insulin action, and PKC appears to be activated by DAG derived from both pathways. Although DAG may be derived from each of these signalling pathways, it is clear that PI-glycan HGM will only be derived from pertussis toxin-sensitive PI-glycan hydrolysis. These findings may help to explain why some, but not all, insulin effects are inhibited by pertussis toxin and are therefore apparently dependent upon Gi alpha. Whether or not other G-proteins are important in other phospholipid signalling pathways during insulin action, e.g., PC hydrolysis, remains to be determined.
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PMID:Pertussis toxin-sensitive and -insensitive mechanisms for diacylglycerol-protein kinase C signalling during insulin action in BC3H-1 myocytes. 213 31

Phorbol ester tumour promoters like phorbol-12-myristate-13-acetate (PMA) and serum-derived factors inhibit growth and induce terminal differentiation in normal human and mouse keratinocytes but have a much reduced effect on their transformed counterparts. These observations may be relevant to potency of PMA and wounding as tumour promoters in mouse epidermis. Since some serum factors produced during wounding are thought to exert their effects through the production of diacylglycerol (DAG-the proposed physiological ligand for the phorbol ester receptor) from phospholipids by the activation of phospholipase C (PC) we have compared the effects of PC with PMA in cultures of normal and transformed human keratinocytes. The addition of PC from Clostridium perfringens (0.1-3.0 units/ml) to the culture medium of normal human keratinocytes produced similar morphological changes to PMA and also mimicked the effects of the phorbol ester on cloning efficiency and cornified envelope formation. Most importantly PC, like PMA, had a very weak effect on the human squamous cell carcinoma lines SCC-12B and SCC-15. All the effects of PC were abolished by boiling the enzyme. These results are discussed in relation to the proposed role of serum factors in tumour promotion by deep skin wounding and their mechanistic relationship to phorbol esters.
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PMID:Phospholipase C mimics the differential effects of phorbol-12-myristate-13-acetate on the colony formation and cornification of cultured normal and transformed human keratinocytes. 244 Jun 13

Transcription of the low-density lipoprotein receptor (LDL-R) gene in the human monocytic leukemic cell line THP-1 and in the human hepatocarcinoma cell line Hep-G2 is regulated by second messengers of the diacylglycerol-protein kinase C (DAG-PKC), inositol 1,4,5-triphosphate-Ca2+, and cyclic AMP pathways. Exogenous phospholipase C (which releases DAG and inositol 1,4,5-triphosphate), PKC activators (phorbol esters and DAG), Ca2+ ionophores, and a cyclic AMP analog all transiently induced accumulation of LDL-R mRNA. The effects of these three signal-transducing pathways were to a large extent additive. Furthermore, PKC stimulation effected an increase in LDL binding, which suggested that the increase in LDL-R mRNA resulted in an increase in functional cell surface receptor activity. These results suggest that uptake of cholesterol by these cells is under control of both intracellular cholesterol levels and external signals.
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PMID:Involvement of second messengers in regulation of the low-density lipoprotein receptor gene. 254 77

Several monoclonal antibodies directed against a number of T cell surface molecules are used to elucidate the role of these molecules (cell surface molecules) in T cell activation. The activation of T cells via these molecules are both antigen-dependent (CD3/TcR complex) and antigen-independent. Irrespective of their antigen dependency, these monoclonal antibodies activate T cells by a classical signal transduction pathway, in which the binding of monoclonal antibodies to their cell surface receptors leads to activation of phospholipase C resulting in the depolarization of plasma membrane, hydrolysis of IP2 and IP3 and DAG, the 'second messengers'. IP3 leads to mobilization of intracellular calcium to contribute to an increase in [Ca++]i, whereas DAG causes activation and translocation of PKC and an increasing apparent affinity for Ca++. The role of IP4 in the mobilization of intracellular calcium is emerging. In addition, influx of extracellular calcium also contributes to increase in [Ca++]i. The increase in [Ca++]i following activation via some T cell surface antigen is predominantly due to intracellular mobilization of Ca++ (e.g. CD3/TcR complex), whereas activation via other T cell surface antigen, the increase in [Ca++]i is almost entirely due to an influx of extracellular calcium (e.g. CD5 antigen). All these molecules activate autocrine system of T cell growth, namely IL-2 production, IL-2 receptor expression and T cell proliferation.
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PMID:Mechanisms of transmembrane signalling in human T cell activation. 269 33

Cerebral ischemia and ischemia-reperfusion induced cerebral injury results in the accumulation of free fatty acids and diacylglycerols as a result of increased activity of phospholipases A and C. We have evaluated the incorporation of 14C arachidonic acid into the whole brain and synaptoneurosomes, the effect of cerebral ischemia on 14C incorporation, and the effect of a PAF antagonist (BN 52021) on cerebral blood flow, free fatty acids, diacylglycerols, and polyphosphoinositides. Peak incorporation of 14C arachidonic acid into the whole brain and synaptoneurosomal fractions occurred 30 minutes following intraventricular injection. Peak incorporation into cerebellar synaptoneurosomal fractions was at 60 minutes following intraventricular injection. Turnover in phospholipid pools was similar in the whole brain and synaptoneurosomes (PI greater than PC greater than PE). Considering phosphatidylinositol content in the gerbil brain, the specific activity of 14C arachidonic acid was 22 times greater in PI than PC. Five minutes of bilateral carotid artery ligation resulted in decreased phosphatidylinositol and polyphosphoinositols. Bilateral carotid artery ligation resulted in systemic arterial hypertension, complete forebrain ischemia (CBF less than 7 ml/100 gm/min) and a 20% to 50% reduction in midbrain CBF. Reperfusion resulted in cerebral reactive hyperemia and systemic hypotension. BN 52021 inhibited the maturation of ischemia-reperfusion induced cerebral injury. Cerebral blood flow was improved. Free fatty acids were decreased, suggesting inhibition of phospholipase A activity. Decreased DAG pools with increased PIP2 pools suggest a possible coinhibition of phospholipase C.
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PMID:Arachidonic acid metabolism and cerebral blood flow in the normal, ischemic, and reperfused gerbil brain. Inhibition of ischemia-reperfusion-induced cerebral injury by a platelet-activating factor antagonist (BN 52021). 277 4

Evidence from a variety of laboratories indicates that crosslinking of B cell mIg induces a rapid increase in intracellular free calcium (Ca++i). This mobilized Ca++ appears to act in concert with diacylglycerol (DAG; also released upon mIg cross-linking) to optimally activate Ca++/phospholipid-dependent protein kinase C, which plays a pivotal role in B cell activation. Here we report analysis of the source of this mobilized calcium and the mechanism responsible for its release into the cytosol. We observed the cross-linking of mIg induces the release of inositol 1,4,5-trisphosphate (InsP3), presumably as a result of action of phospholipase C on plasma membrane phosphatidylinositol 4,5-bisphosphate (PtdInsP2). The release of InsP3 and the elevation of Ca++i are coincidental, suggesting that they may be causally related. Finally, we demonstrate that submicromolar doses of InsP3 induce release of Ca++ from permeabilized cells that had preaccumulated 45Ca++ in the endoplasmic reticulum. On the basis of these findings we suggest that mIg cross-linking leads to mobilization of Ca++, in part by causing hydrolysis of PtdInsP2, yielding InsP3, which in turn causes release of calcium from the endoplasmic reticulum.
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PMID:Anti-Ig induces release of inositol 1,4,5-trisphosphate, which mediates mobilization of intracellular Ca++ stores in B lymphocytes. 301 2

In human placenta membranes the rate limiting enzyme for PIP2 formation from PI is PIP kinase. GTP gamma S is shown to activate PIP kinase by increasing Vmax of the enzyme. It is suggested that a guanine nucleotide regulatory protein is involved in the activation of PIP kinase although coupling with a specific receptor is not yet known. Since PIP2 is the preferred substrate of phospholipase C, the possibility exists that an increase of PIP2 due to activation of PIP kinase leads to an enhancement of phospholipase C activity and hence to an increased production of IP3 and DAG.
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PMID:Stimulation of phosphatidylinositol 4-phosphate phosphorylation in human placenta membranes by GTP gamma S. 302 33

The adenylate cyclase - cAMP, phospholipase C - IP3 (inositol 1,4,5-triphosphate), and DAG (diacylglycerol) signal transduction systems are used to illustrate general principles underlying the process of information transfer during cell stimulation. Both systems consist of reaction cascades that convert the external signal to an intracellular messenger, translate the messenger to regulatory activities, and then modulate the activities of appropriate cellular proteins to result in specific cell responses. Almost all of these reactions are under second-messenger-dependent regulation, with many being regulated by multiple messengers. Such complex regulation provides ample opportunities for the fine-tuning of the signal cascades and for coordination between cascades during cell stimulation. Specific examples are used to illustrate how the cell uses different intrasystem and intersystem regulatory reactions to achieve specific responses.
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PMID:Integration of signal-transduction processes. 304 30

The content and composition of 1,2-diacyl-sn-glycerol (1,2-DAG) was determined in hepatocytes from saline (0.9% NaCl)- and Escherichia coli endotoxin (ET)-infused rats upon continuous vasopressin (VP) (10(-8) M) stimulation. In both experimental groups the accumulation of 1,2-DAG was detected after a lag period (2-5 min), was sustained up to the last time analysed (10 min), and C18:0- and C20:4-fatty-acid-containing-DAG accumulation preceded that of DAG containing other acyl groups. In hepatocytes from ET-infused rats the VP-induced accumulation of DAG was delayed and was decreased by 50%, showing a C18:0/C20:4 molar ratio of 1.6 as compared with 1.1 for cells from saline-infused rats. A similar lower cellular response to VP stimulation was observed in cells prelabelled with [14C]C20:4 fatty acid. The accumulation of [14C]C20:4-DAG (lower in ET than in saline-infused rats) was paralleled by a decrease in phosphatidylinositol (PI) labelling, whereas phosphatidic acid showed a transient increase by 5 min in saline- but not in ET-infused rats. The present results demonstrate that the previously reported impairment in the early degradation of poly-PI and later in the 'PI cycle' during VP stimulation [Rodriguez de Turco & Spitzer (1987) Metab. Clin. Exp. 36, 753-760] is also reflected at the level of their phosphodiesteratic product, DAG. Moreover, the kinetics of the accumulation of DAG acyl groups is consistent with the idea that the initial release of C18:0- and C20:4-DAG (possibly derived from inositol lipids) could regulate the subsequent enlargement of this pool by stimulating a phospholipase C-mediated degradation of other phospholipids (e.g. phosphatidylcholine).
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PMID:Kinetics of diacylglycerol accumulation in response to vasopressin stimulation in hepatocytes of continuously endotoxaemic rats. 313 86

The regulation of corticosteroid secretion of the adrenal cortex (interrenal tissue) of axolotl (Ambystoma mexicanum) was studied using in vitro preparations of kidney containing interrenal tissue. Normally, 0.3-0.65 ng/5 min corticosterone and 0.15-0.3 ng/5 min aldosterone were released from the tissue. Regulatory peptides were effective in the following range: ACTH = arginine vasotocin > urotensin II > angiotensin II. They stimulate an elevation of corticosterone (plus 0.2-1 ng/5 min) and of aldosterone (plus 0.05-0.15 ng/5 min). The three primary effector systems leading to second messengers, adenylate cyclase (forming cAMP), phospholipase C (forming InsP3 + DAG), and phospholipase A2 (liberating arachidonic acid) are involved in stimulation of biosynthesis. It can be suggested that the second messengers stimulate the biosynthesis at the level of the steps between pregnenolone and corticosterone ('3 beta-hydroxysteroid-dehydrogenase etc.), because the release of corticosterone is more stimulated than aldosterone. This is different than the regulation of anuran interrenal tissue. Ca++ ions are involved in corticosterone secretion. Verapamil inhibits immediately the secretion of corticosteroids and elevation of external Ca++ stimulates the release. It is suggested that Ca++ mediates the secretion process itself. Metamorphosis does not change the response of the interrenal gland compared with the neotenic animal.
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PMID:Regulation of interrenal secretion in the axolotl, Ambystoma mexicanum. 781 1


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