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)

When intact human erythrocytes were treated with phospholipase C (Clostridium perfringens), up to 30% of the membrane phospholipids were broken down without significant cell lysis. Only phosphatidylcholine and sphingomyelin were attacked. Ceramide (derived from sphingomyelin) accumulated, but 1,2-diacylglycerol (derived from phosphatidylcholine) was largely converted into phosphatidate. Up to 12% of the cell phospholipid could be converted into phosphatidate in this way. Pig erythrocytes and lymphocytes showed a similar but smaller synthesis of phosphatidate after phospholipase C attack. Phospholipase C also caused a marked morphological change in erythrocytes, giving rise to spherical cells containing internal membrane vesicles. This change appeared to be due to ceramide and de and diacylglycerol accumulation rather than to increased phosphatidate content of the cells.
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PMID:Changes in lipid metabolism and cell morphology following attack by phospholipase C (Clostridium perfringens) on red cells or lymphocytes. 17 56

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are cytokines with pleiotropic biological activities, exerting a broad range of overlapping biological functions. The redundancy of TNF and IL-1 activities may be based on the utilization of shared key components of intracellular signaling pathways. Two lipid second messengers have been found to transmit TNF and IL-1 intracellular signals: 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C, and ceramide, generated by sphingomyelinase (SMase). DAG is a well established activator of the important signaling system protein kinase C (PKC), which appears to mediate various cellular responses to TNF or IL-1. In addition, it is obvious that DAG also activates other enzyme systems like acidic sphingomyelinase. SMases have been implicated in a number of TNF responses, including stimulation of cell growth and differentiation, as well as triggering cytotoxicity and apoptosis. The metabolic active cleavage product of SMase, ceramide, is a novel multifunctional lipid second messenger capable of inducing various signaling systems. Both cytokines, TNF and IL-1, stimulate a neutral,plasma membrane-associated SMase that leads to stimulation of a protein kinase and eventually to activation of the mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Ceramide is also capable of stimulating a cytosolic protein phosphatase. PKC plays a role in activation of the nuclear transcription factor AP-1, and the DAG-regulated acidic SMase is involved in transducing TNF signals to the cell nucleus via activation of the nuclear transcription factor NF-kappa B.
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PMID:The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. 796 60

Prior studies demonstrated that increased intracellular availability of ceramide induces apoptotic DNA degradation and cell death in the human leukemia cell lines HL-60 and U937 (Jarvis, W. D., Kolesnick, R. N., Fornari, F. A., Traylor, R. S., Gewirtz, D. A., and Grant, S. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 73-77). The present findings show that diglyceride opposes ceramide-related apoptosis in HL-60 and U937 cells. Acute (6-12-h) exposure to sphingomyelinase (100 milliunits/ml) or synthetic ceramide (10 microM) promoted apoptotic degradation of genomic DNA as indicated by (a) the appearance of both approximately 50-kilobase pair (kbp) DNA fragments and approximately 0.2-1.2-kbp DNA fragment ladders on agarose gels, (b) formation and release of small double-stranded DNA fragments, and (c) loss of integrity of bulk DNA. DNA damage was associated with reduced clonogenicity and expression of apoptotic morphology. In contrast, exposure to phospholipase C (0.001-100 milliunits/ml) or synthetic diglyceride (10 microM) failed to promote apoptosis and abolished the lethal actions of ceramide as defined by each of the indices outlined above. Ceramide-related apoptosis was also reduced by acute (6-h) exposure to tumor promoters such as phorbol dibutyrate and mezerein and the non-tumor-promoting agent bryostatin 1; conversely, chronic (24-h) pretreatment with these agents failed to modify ceramide-mediated cytotoxicity, but abolished the protective actions of diglyceride. These findings demonstrate that diglyceride and pharmacological protein kinase C activators reduce or abolish ceramide-mediated apoptosis in human leukemia cells and support the concept of a cytoprotective function for protein kinase C in the regulation of leukemic cell survival. In addition, the capacity of diglyceride to prevent very early genomic lesions (e.g. generation of 50-kbp DNA fragments) suggests that acute activation of protein kinase C arrests apoptosis at an initial stage.
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PMID:Attenuation of ceramide-induced apoptosis by diglyceride in human myeloid leukemia cells. 798 41

The cytokine-mediated stimulation of sphingomyelin (SM) metabolism is emerging as an important signal transduction pathway via the generation of ceramide and sphingosine, products which have been shown to affect a wide variety of biological processes. Because SM-mediated signal transduction is initiated via the hydrolysis of an integral membrane phospholipid by a phospholipase C-like enzyme (sphingomyelinase) to yield lipids which modulate protein kinase C activity, the SM and phosphatidylinositol (PI) signaling pathways share certain similarities. The present study was undertaken to examine the potential for interplay between SM and PI turnover by testing the effects of sphingosine, sphingosine-1-phosphate, and ceramide on PI turnover. In dermal fibroblasts, sphingosine stimulated a rapid dose-dependent hydrolysis of PI, yielding inositol 1,4,5-triphosphate, followed by increased levels of intracellular calcium. Sphingosine-induced inositol phosphate (IP) accumulation was observed between 5 and 30 microM sphingosine with a maximal accumulation of 2.7-fold over control levels. Enhanced IP formation was measured as early as 5 s following sphingosine treatment and IP levels remained elevated for more than 60 min. Intracellular calcium mobilization accompanied the dose-dependent accumulation of IPs in response to sphingosine, although this effect was not apparent until after a 30-40-s lag period. Interestingly, sphingosine-1-phosphate stimulated a more rapid release of intracellular Ca2+ than sphingosine, but it had no effect on PI turnover. DL-threo-Dihydrosphingosine, a competitive inhibitor of sphingosine kinase, stimulates both PI turnover and Ca2+ flux, but does not block the action of sphingosine relative to those two processes. Ceramide (added as C2-ceramide), N-stearylamine, and stearoyl-D-sphingosine did not affect PI turnover or Ca2+ mobilization. Pretreatment of intact cells with pertussis toxin partially inhibited sphingosine-mediated IP accumulation, suggesting a role for guanine nucleotide binding protein(s) (G protein) in sphingosine-stimulated PI turnover. Furthermore, guanosine 5'-O-(3-thiotriphosphate) stimulated, whereas guanosine 5'-O-(2-thiodiphosphate) inhibited, sphingosine-induced IP accumulation in permeabilized cells. Collectively, these data suggest that sphingosine enhances PI turnover by stimulating phospholipase C activity, and the activation of this process may be modulated by G protein interactions. Thus, the regulation of PI turnover and Ca2+ mobilization by sphingosine may represent another mechanism by which sphingosine modulates cell function and that these effects can be distinguished from those of ceramide.
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PMID:Sphingosine-mediated phosphatidylinositol metabolism and calcium mobilization. 811 27

Tumor Necrosis Factor (TNF) is one of the most potent physiological inducers of the nuclear transcription factor NF-kappa B. In light of the pivotal role of NF-kappa B in the development of immune responses and activation of HIV replication, the identification of TNF signal transduction pathways involved in NF-kappa B activation is of particular interest. Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. Besides endosomal acidic SMase, TNF also rapidly activates a plasmamembrane-associated neural SMase (nSMase), that, however is not involved in TNF-induced NF-kappa B activation. NSMase and aSMase are activated by different cytoplasmic domains of the 55 kDa TNF-receptor and are coupled to select pathways of TNF signaling. Ceramide generated by nSMase directs the activation of proline-directed serin/threonine protein kinases and phospholipase A2 and ceramide produced by aSMase triggers the activation of NF-kappa B. No apparent crosstalk was detected between nSMase and aSMase pathways, indicating that ceramide action depends on the topology of its production.
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PMID:TNF-induced activation of NF-kappa B. 853 Jan 43

Complete prevention of the killing of L929 fibroblasts by tumor necrosis factor alpha (TNF) in the presence of 0.5 microg/ml actinomycin D (ActD) was obtained with cyclosporin A (CyA), an inhibitor of the mitochondrial permeability transition (MPT), and aristolochic acid (ArA), a phospholipase A2 inhibitor. Peripheral benzodiazepine receptor (PBzR) agonists (PK11195, FGIN 1-27, or chlorodiazepam), agents known to potentiate induction of the MPT, potentiated the cytotoxicity of TNF in the absence of ActD, an effect prevented by CyA plus ArA. The MPT was demonstrated independently of its effect on viability as the CyA-sensitive loss of rhodamine 123 fluorescence from cells preloaded with the dye. Treatment with TNF and ActD resulted in the loss of 80% of rhodamine fluorescence within 6 h, a time prior to any loss of viability. CyA plus ArA completely prevented this effect of TNF. Potentiation of the cytotoxicity of TNF by PBzR agonists was associated with induction of the MPT, as assessed by the loss of rhodamine fluorescence. CyA plus ArA completely prevented the loss of rhodamine 123. Ceramide replaced TNF in killing L929 fibroblasts, an effect also prevented by CyA plus ArA. Ceramide in the presence of ActD resulted in the loss of rhodamine fluorescence, an effect that was again prevented by CyA plus ArA. In addition, CyA plus ArA prevented the ability of PBzR agonists to potentiate the cytotoxicity of ceramide. In the presence of each PBzR agonist, ceramide caused the loss of rhodamine fluorescence, an effect completely prevented by CyA plus ArA. D609, an inhibitor of phosphatidylcholine-specific phospholipase C, completely prevented the killing by TNF, but not by ceramide, in the presence of ActD. D609 prevented induction of the MPT occurring with TNF, but not with ceramide. Inhibitors of endocytosis, as well as lysosomotropic amines, prevented the cytotoxicity of TNF, but not that of ceramide. It is concluded that the MPT is causally linked to the genesis of irreversible cell injury with TNF. In the face of an inhibition of protein synthesis, the MPT occurs as a consequence of the formation of ceramide.
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PMID:The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition. 893 17

Concentrations of the bioactive lipids, phosphatidate and diacylglycerol, increased with time in culture in ras- and tyrosine kinase (fps)-transformed fibroblasts but not in control fibroblasts. On Day 3, diacylglycerol and phosphatidate concentrations were about 3.3- and 5.5-fold higher respectively in the ras-transformed compared to control fibroblasts. These concentrations in fps-transformed fibroblasts were increased about twofold. The changes in phosphatidate and diacylglycerol resulted from enhanced phospholipid turnover rather than from synthesis de novo. The increased ratio of phosphatidate to diacylglycerol is explained by decreased activities of two distinct phosphatidate phosphohydrolases and increased diacylglycerol kinase in ras-transformed fibroblasts. Ceramide concentrations were about 2.5- and threefold higher in the fps- and ras-transformed cells respectively on Day 3 compared to the controls. Incubating control fibroblasts from Days 1 to 3 with phosphatidylcholine-specific phospholipase C increased diacylglycerol, phosphatidate and ceramide concentrations, and decreased Mg2+-independent-phosphatidate phosphohydrolase activity. 8-(4-chlorophenylthio)-cAMP had a cytostatic effect in ras-transformed cells, it decreased the concentrations of phosphatidate and diacylglycerol, but increased that of ceramide. The consequences of increased ceramide and phosphatidate concentrations in ras-transformed cells are discussed in relation to signal transduction, cell division and the transformed phenotype.
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PMID:Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts. 912 48

In an attempt to obtain sufficient quantities of pure phospholipase C delta 1 (PLC delta 1) necessary for structural and kinetic studies, human fibroblast PLC delta 1 was cloned in the pPROEX-1 vector, expressed in E. coli cells as a (6xHis) fusion protein and purified to homogeneity. From 11 of E. coli culture 21 mg of pure PLC delta 1 was obtained by a two-step purification procedure, which includes Ni(2+)-NAT agarose and Mono S cation exchange chromatography. Catalytic properties of recombinant PLC delta 1 with respect to activation by spermine and calcium ions and inhibition by sphingomyelin were similar to or identical to PLC delta 1 purified from rat liver. Calcium activation of PLC delta 1 was dependent on the presence of spermine. Half-maximal activity was attained at 250 and 170 nM of free Ca2+ in the presence and absence of spermine, respectively. Sphingomyelin and lysosphingomyelin were mixed type inhibitors with respect to PIP2. Ceramide inhibits PLC delta 1 very weakly. GM1, which is a ceramide bound glucosidically to the oligosaccharide moiety, was a strong non-competitive inhibitor of PLC delta 1. In the absence of spermine, sphingosine and phytosphingosine weakly activated PLC delta 1. The results indicate that the effect of sphingomyelin and its metabolites on PLC delta 1 activity depends on the presence of spermine. It is postulated that, among other factors, in vivo, activity of PLC delta 1 may depend on the turnover of sphingomyelin.
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PMID:Effect of sphingomyelin and its metabolites on the activity of human recombinant PLC delta 1. 925 Dec 49

The present study examined the SM cycle as a mechanism to explain the inhibitory effect of SIT on HT-29 cell growth. SIT was the main phytosterol in the diet. Supplementation of SIT at 16 microM for 5 days in the media inhibited growth by 55% as compared to cholesterol. SIT supplementation had no effect on sphingosine production. Ceramide production increased 45% with SIT supplementation as compared to cholesterol. Sterol supplementation had no effect on phospholipase C, a key enzyme in the PKC pathway. We concluded that the activation of the SM cycle may play a role in growth inhibition of HT-29 cells by SIT.
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PMID:beta-Sitosterol inhibits growth of HT-29 human colon cancer cells by activating the sphingomyelin cycle. 956 22

To study the involvement of sphingolipids in glycerophospholipid metabolism, the contribution of ceramide to the activation of group IV cytosolic phospholipase A2 (cPLA2) was investigated in platelets using cell-permeable C6-ceramide (N-hexanoylsphingosine). The addition of ceramide led to potentiation of thrombin-induced activation of cPLA2 and mitogen-activated protein kinase (MAPK) as well as arachidonic acid release and lysophosphatidylcholine formation. However, ceramide by itself did not induce any response. The arachidonic acid release due to the synergistic action of ceramide and thrombin was inhibited by PD98059, a MAPK kinase inhibitor. Ceramide also stimulated thrombin-induced protein kinase C (PKC) activation, but ceramide by itself failed to do so. Furthermore, ceramide synergistically enhanced diacylglycerol (DAG) formation and Ca2+ mobilization with thrombin, and also DAG formation with Ca2+-ionophore A23187. The DAG formation in response to ceramide with thrombin or A23187, as well as arachidonic acid release with thrombin were completely inhibited by U73122, a phospholipase C (PLC) inhibitor. These results suggest that ceramide triggers PLC activation through its synergistic action with thrombin, and subsequently potentiates the sequential PKC-MAPK cascade-cPLA2 pathway, thus resulting in enhancement of arachidonic acid release.
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PMID:Stimulation by ceramide of phospholipase A2 activation through a mechanism related to the phospholipase C-initiated signaling pathway in rabbit platelets. 988 Aug 3


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