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At least 127 records · Page 7Linked to original sources
PubMed1992

Comparison of diglyceride production from choline-containing phosphoglycerides in human neutrophils stimulated with N-formylmethionyl-leucylphenylalanine, ionophore A23187 or phorbol 12-myristate 13-acetate.

The turnover of choline-containing phosphoglycerides (PC) in response to agonist stimulation is well documented in human neutrophils. We have now compared the enzymic pathways of N-formylmethionyl-leucylphenylalanine (fMLP)-, A23187- and phorbol-12-myristate 13-acetate (PMA)-induced diglyceride (DG) and phosphatidic acid (PA) generation in these cells. In order to distinguish between phospholipase C- and D-mediated PC breakdown, human neutrophils were radiolabelled with 1-O-[3H]alkyl-2-acyl-glycero-3-phosphocholine and stimulated in the presence of ethanol or propranolol. The addition of 0.5% ethanol to the incubation mixture resulted in the production of phosphatidylethanol, indicative of phospholipase D activation, in response to all three stimuli. Concomitant with phosphatidylethanol formation was a partial block of PA production. The production of DG was also partially blocked by addition of ethanol. Propranolol (200 microM) was also used to assess the contributions of phospholipases C and D toward DG generation. Inhibition of PA phosphohydrolase by propranolol resulted in the complete abolition of DG generation when neutrophils were stimulated with fMLP. In contrast, propranolol only partially inhibited DG generation in response to A23187 and PMA. These results suggested that DG production in response to fMLP stimulation is mediated via the activation of phospholipase D, whereas A23187- or PMA-induced DG generation may involve more than one pathway. However, examination of the water-soluble choline metabolites produced indicated that phospholipase D was responsible for the production of PA and DG in response to all three stimuli.

Calcimycin↗
PubMed1994

Monogalactosyl diglyceride, a marker for myelination, activates oligodendroglial protein kinase C.

Protein kinase C (PKC) is activated by 1,2-sn-diacylglycerol (DAG), the source of which can either be phosphatidylinositol bisphosphate or phosphatidylcholine. Here, we show that monogalactosyl diglyceride (MGDG), a minor galactolipid present in oligodendrocytes (OLs) and myelin, which is designated as a marker for myelination, can enhance OL PKC activity. Based on different calcium and substrate requirements we conclude that MGDG and DAG activate different isoforms of PKC group A: MGDG primarily stimulates PKC-alpha, and DAG primarily activates PKC-gamma. The presence of these PKC isoforms in OLs was confirmed by western blotting, whereas PKC-beta was only weakly stained, if at all. Addition of MGDG to the culture medium provided a higher density of regenerating OL fibers, which was not observed when membrane-permeable DAG was used. These findings indicate that MGDG can modulate the OL PKC activity and that PKC-alpha is the major PKC isoform involved in OL process formation.

Animals↗
PubMed1977

Biosynthesis of the covalently linked diglyceride in murein lipoprotein of Escherichia coli.

Biosynthesis of the diglyceride moiety of murein lipoprotein in Escherichia coli was studied by pulse-labeling with [2-3H]glycerol and subsequent chase. The evidence strongly suggests that the precursor of the glycerol moiety in lipoprotein is one of the major phospholipid species in E. coli. Studies of biosynthesis of lipoprotein in cerulenin-treated cells indicated that the nonacylated glycerol moiety of phosphatidylglycerol is the donor for the formation of a thioether linkage in the glycerylcysteine residue of the lipoprotein. This is supported by the observation that carbon 1 rather than carbon 3 of sn-glycerol is involved in this thioether linkage. We propose that the biosynthesis of lipoprotein proceeds as follows: apolipoprotein + phosphatidylglycerol or acyl phosphatidylglycerol leads to lipoprotein + phosphatidic acid.

Apolipoproteins↗
PubMed1994

Retinoids inhibit protein kinase C-dependent transduction of 1,2-diglyceride signals in human colonic tumor cells.

1,2-Diglycerides with long-chain fatty acid residues related to nutritional fat (LCDGs) specifically affect growth and urokinase secretion in human colonic tumor cells, but not in normal mucosa. This allows them to advance and enhance carcinogenesis in the colon and rectum. SW480 colon carcinoma cells are LCDG sensitive in the same way as primary colonic tumor cells and have therefore been used as a model system to study the mechanism of LCDG action and to search for inhibitors of tumor development in the colon. Using this model system, we have shown that the effects of LCDGs are transmitted by protein kinase C and abolished by downregulation of the enzyme. Retinol, retinoic acid, and beta-carotene in nanomolar concentrations inhibit LCDG-induced growth and urokinase secretion and block stimulation of protein kinase C. Although retinol and retinoic acid at higher concentrations also display stimulatory activity, beta-carotene does not. At 100 nM, a concentration that can easily be reached in the plasma of humans, beta-carotene reduces LCDG-induced urokinase secretion about 50%. Inasmuch as beta-carotene does not have side effects due to intrinsic activities and storage effects, beta-carotene and foods rich in carotenes could be useful in the prevention of colorectal cancer.

Carotenoids↗
PubMed1986

Comparison of the activity of phorbol 12-myristate 13-acetate and the diglyceride glycerol 1-myristate 2-acetate.

Diglycerides function as analogs of the phorbol ester tumor promoters. We compare here the activity of glycerol 1-myristate 2-acetate (GMA) with the corresponding phorbol 12-myristate 13-acetate (PMA). GMA inhibited phorbol ester binding to reconstituted protein kinase C, stimulated protein kinase C enzymatic activity, and, upon addition to intact 3T3 cells, inhibited [125I]EGF binding. Its potency was much less than that of PMA, however (2.9 X 10(4)-fold less for phorbol ester binding, greater than 1.2 X 10(5)-fold less for inhibition of EGF binding), and its activity on the intact cells was more transient. The marked difference in potency contrasts with the much smaller differences found previously for the corresponding pairs of dilaurate and dioleate derivatives.

Animals↗
PubMed1976

Solubilization of diglyceride acyltransferase from the membrane of Mycobacterium smegmatis.

Diglyceride acyltransferase [acyl-CoA : 1,2-diacylglycerol O-acyltransferase, EC 2.3.1.20] was found to be localized in the membrane of Mycobacterium smegmatis, and this enzyme could be solubilized from the membrane by treatment with aqueous acetone. The solubilized enzyme required either 1,2-diolein or 1, 3-diolein as an acceptor for palmitoyl-CoA. The apparent Km value for 1,2- or 1,3-diolein and that for palmitoyl-CoA were about 1.4 X 10(-5) M and 6 X 10(-6) M, respectively. Several sulfhydryl reagents were inhibitory to the enzyme activity, suggesting the existence of a thiol group(s) in its active site. The solubilized enzyme, which was more labile than that membrane-bound one, could be stabilized to some extent with antichaotropic salts such as phosphate, pyrophosphate, and sulfate.

Acyltransferases↗
PubMed1990

Bradykinin induces phosphoinositide turnover, 1,2-diglyceride formation, and growth in cultured adult human keratinocytes.

The effects of bradykinin on activation of phosphoinositide turnover, 1,2-diglyceride formation, and growth of cultured adult human keratinocytes were investigated. Keratinocytes specifically bound [3H]bradykinin with high affinity (kd = 3.4 nM) and displayed 1.5 X 10(5) binding sites/cell. Bradykinin caused a rapid dose-dependent increase in inositol trisphosphate (IP3) inositol bisphosphate, and inositol monophosphate. IP3 was maximally increased (fivefold) at 30 s and remained elevated for at least 10 min. Half maximal stimulation of IP3 formation was observed at 27 nM bradykinin. IP3 accumulation was equally elevated by bradykinin and lys-bradykinin but was not stimulated by des-Arg9-bradykinin, indicating that phospholipase C in cultured keratinocytes is coupled to B2 bradykinin receptors. Treatment of keratinocytes with active phorbol ester (TPA) caused a significant inhibition (50%) of bradykinin-induced IP3 accumulation, suggesting negative regulation of phospholipase C by protein kinase C. Bradykinin also caused a significant elevation in 1,2-diacylglycerol (DAG) content. DAG content was maximally elevated (twofold) at 1 min and remained elevated for at least 10 min. Bradykinin also caused a significant (twofold, p less than 0.02) increase in keratinocyte growth. These data demonstrate that bradykinin is a potent agonist of the phospholipase C/protein kinase C signal transduction system in cultured adult human keratinocytes and that activation of this pathway by bradykinin is associated with increased keratinocyte growth.

Adult↗
PubMed1979

Diglyceride kinase from Escherichia coli. Purification in organic solvent and some properties of the enzyme.

The diglyceride kinase activity of membranes from Escherichia coli was extracted into acidic butan-1-ol. The enzyme was purified in organic solvent by precipitation at -20 degrees C, chromatography on DEAE-cellulose and repeated chromatography on Sephadex LH-60. The final 1460-fold purified enzyme preparation gave a single protein band upon isoelectric focusing in the presence of Triton X-100 (pI, 4.0) and upon polyacrylamide-gel electrophoresis in the presence of sodium dodecylsulphate. The latter method as well as gel chromatography on Sephadex LH-60 indicated a molecular weight of about 15400. The purified enzyme was devoid of lipid, and it required re-addition of lipid for activity. sn-1,2-Dipalmitate and ceramide were phosphorylated, whereas the C55-isoprenoid alcohol, ficaprenol, did not serve as a substrate under the same conditions. Conversely, the butanol-soluble C55-isoprenoid-alcohol kinase from Staphylococcus aureus did not phosphorylate sn-1,2-dipalmitate.

Cell Membrane↗
PubMed1981

Properties of a CDP-diglyceride hydrolase from guinea pig brain.

Enzymatic hydrolysis of the pyrophosphate bond of CDP-diglyceride (CDP-DG), previously shown to occur in bacteria, is demonstrable in mammalian tissues. Activity was enriched in a lysosomal fraction obtained from guinea pig cerebral cortex and was purified 92-fold relative to the homogenate by a combination of XM-300 ultrafiltration and DEAE-cellulose column chromatography. When incubated with CDP-dipalmitin, the purified enzyme produced stoichiometric amounts of CMP and phosphatidate. dCDP-DG served as a substrate, while ADP-DG was an inhibitor, as were 5'-AMP and 5'-dAMP. CDP-DG hydrolysis was not affected by the presence of excess amounts of CDP-choline, CDP-glycerol, sodium pyrophosphate, or cyclic 3',5'-AMP.

Animals↗
PubMed1975

Degradation of phospholipid and release of diglyceride-rich membrane vesicles during protoplast formation in certain gram-positive bacteria.

Membrane phospholipid was found to be hydrolyzed presumably by an intracellular phospholipase C, and diglyceride-rich membrane vesicles were released from the cells during protoplast formation in Bacillus cereus Bacillus subtilis, Micrococcus lysodeikticus, and Staphylococcus aureus. The released membranes consisted mainly of small vesicles of 50 to 100 nm in diameter. They have a lower density than that of protoplast membranes in all the bacteria tested in the present study.

Acetates↗
PubMed1977

Specific deficit in the synthesis of 6-sulfoquinovsyl diglyceride in Chlorella pyrenoidosa.

It was found that when Chlorella pyrenoidosa was grown on cysteine as the sole sulfur source, it lost the ability to grow photoautotrophically. When grown in the presence of glucose, cysteine-grown cells displayed a doubling time in the light or dark of 45 h, which is identical to that of cells grown on glucose and SO4 in the dark. This suggests that cells grown on cysteine as sole sulfur source can only grow heterotrophically. In support of this hypothesis, it was found that cysteine-grown cells were defective both in vivo and in vitro in CO2 fixation, although O2 evolution in such cells was normal. Assays of the enzymes of the Calvin cycle indicated that the deficit in CO2 fixation could be ascribed to a lowered phosphoribulokinase activity. A total lipid analysis of Chlorella grown on cysteine revealed that such cells showed a 100-fold deficiency in the purportedly chloroplast-associated 6-sulfoquinovsyl diglyceride. This agrees with earlier reports that cysteine could not serve as a precursor of sulfolipid in Chlorella. No other polar lipid was affected. Large amounts of triglyceride, however, were found in cysteine-grown cells. The biosynthesis of triglyceride provides a means of utilizing reduced nicotinamide adenine dinucleotide reducing equivalents not being used for CO2 fixation.

Chlorella↗
PubMed1980

A rapidly metabolizing pool of phosphatidylglycerol as a precursor of phosphatidylethanolamine and diglyceride in Bacillus megaterium.

Pulse-chase experiments in Bacillus megaterium ATCC 14581 with [U-14C]palmitate, L-[U-14C]serine, and [U-14C]glycerol showed that a large pool of phosphatidylglycerol (PG) which exhibited rapid turnover in the phosphate moiety (PGt) underwent very rapid interconversion with the large diglyceride (DG) pool. Kinetics of DG labeling indicated that the fatty acyl and diacylated glycerol moieties of PGt were also utilized as precursors for net DG formation. The [U-14C]glycerol pulse-chase results also confirmed the presence of a second, metabolically stable pool of PG (PGs), which was deduced from [32P]phosphate studies. The other major phospholipid, phosphatidylethanolamine (PE), exhibited pronounced lags relative to PG and DG in 14C-fatty acid, [14C]glycerol, and [32P]phosphate incorporation, but not for incorporation of L-[U-14C]serine into the ethanolamine group of PE or into the serine moiety of the small phosphatidylserine (PS) pool. Furthermore, initial rates of L-[U-14C]serine incorporation into the serine and ethanolamine moieties of PS and PE were unaffected by cerulenin. The results provided compelling in vivo evidence that de novo PGt, PS, and PE synthesis in this organism proceed for the most part sequentially in the order PGt yields PS yields PE rather than via branching pathways from a common intermediate and that the phosphatidyl moiety in PS and PE is derived largely from the corresponding moiety in PGt, whereas the DG pool indirectly provides an additional source for this conversion by way of the facile PGt in equilibrium or formed from DG interconversion.

Bacillus megaterium↗
PubMed1994

Direct stimulation of Vav guanine nucleotide exchange activity for Ras by phorbol esters and diglycerides.

We recently identified Vav as a Ras-activating guanine nucleotide exchange factor (GEF) stimulated by a T-cell antigen receptor-coupled protein tyrosine kinase (PTK). Here, we describe a novel, protein kinase-independent alternative pathway of Vav activation. Phorbol ester, 1,2-diacylglycerol, or ceramide treatment of intact T cells, Vav immunoprecipitates, or partially purified Vav generated by in vitro translation or COS-1 cell transfection stimulated the Ras exchange activity of Vav in the absence of detectable tyrosine phosphorylation. GEF activity of gel-purified Vav was similarly stimulated by phorbol myristate acetate (PMA). Stimulation was resistant to PTK and protein kinase C inhibitors but was blocked by calphostin, a PMA and diacylglycerol antagonist. In vitro-translated Vav lacking its cysteine-rich domain, or mutated at a single cysteine residue within this domain (C528A), was not stimulated by PMA but was fully activated by p56lck. This correlated with increased binding of radiolabeled phorbol ester to COS-1 cells expressing wild-type, but not C528A-mutated, Vav. Thus, Vav itself is a PMA-binding and -activated Ras GEF. Recombinant interleukin-1 alpha stimulated Vav via this pathway, suggesting that diglyceride-mediated Vav activation may couple PTK-independent receptors which stimulate production of lipid second messengers to Ras in hematopoietic cells.

Alkaloids↗
PubMed1990

Activation of myocardial protein kinase C by plasmalogenic diglycerides.

Recently, we have demonstrated that myocardial sarcolemma is predominantly comprised of plasmalogen molecular species and that the plasmalogen metabolite 1-O-alk-1'-enyl-2-acyl-sn-glycerol (AAG) accumulates during myocardial ischemia despite substantial decreases in 1,2-diacyl-sn-glycerol (DAG) content. To elucidate the physiological significance of AAG accumulation during myocardial ischemia, rabbit myocardial protein kinase C was partially purified by DE-52 and high-performance hydroxylapatite chromatographies, and the potency of AAG as an activator of myocardial protein kinase C was assessed. Both AAG and 1-O-alkyl-2-acyl-sn-glycerol are potent activators of myocardial protein kinase C with obligatory requirements for physiological increments in free Ca2+ concentration. In contrast, a substantial amount of myocardial protein kinase C activity elicited by DAG was calcium independent. Concentration dependence of ATP for protein kinase C-mediated phosphorylation was identical utilizing either ether-linked diglycerides or DAG as activators, with maximal phosphorylation manifest at ATP concentrations two orders of magnitude less than those found in ischemic myocardium. Thus accumulation of AAG in ischemic myocardium in conjunction with increases in intracellular free Ca2+ concentration may synergistically activate protein kinase C and therefore modulate phosphorylation of proteins in specific subcellular loci.

Adenosine Triphosphate↗
PubMed1988

Effects of mezerein and diglycerides on ornithine decarboxylase activity in mouse mammary gland explants.

One of the most rapid actions of prolactin in mouse mammary gland explants is the stimulation of ornithine decarboxylase (ODC) activity. Several protein kinase C activators including mezerein, dicaprin, diolein, and 1-oleoyl-2-acetyl-rac-glycerol were found to stimulate ODC activity as does prolactin. Both mezerein and the diglycerides produced nonadditive responses when tested with maximum stimulatory concentrations of prolactin. The results of these studies therefore provide further evidence that the prolactin stimulation of ODC activation in the mammary gland may involve an activation of protein kinase C.

Animals↗
PubMed1992

Alpha-thrombin stimulates nuclear diglyceride levels and differential nuclear localization of protein kinase C isozymes in IIC9 cells.

The mechanism by which an agonist, binding to a cell surface receptor, exerts an effect on events in the nucleus is not known. We have previously shown (Leach, K. L., Ruff, V. A., Wright, T. M., Pessin, M. S., and Raben, D. M. (1991) J. Biol. Chem. 266, 3215-3221) that alpha-thrombin treatment of IIC9 cells results in increased levels of cellular 1,2-diacylglycerol (DAG) and activation of protein kinase C (PKC). Here, we have examined whether changes in nuclear PKC and nuclear DAG also are induced following alpha-thrombin treatment. IIC9 cells were treated with 500 ng/ml alpha-thrombin, and nuclei were then isolated. Western blot analysis using isozyme-specific antibodies demonstrated the presence of PKC alpha, but not PKC epsilon or zeta in the nuclei of cells treated with either phorbol 12-myristate 13-acetate or alpha-thrombin. The increase in nuclear PKC alpha levels was accompanied by a 10-fold increase in nuclear PKC specific activity and stimulated phosphorylation of at least six nuclear proteins. The rise in nuclear PKC levels occurred rapidly and reached a maximum at 30-60 s, which was followed by a decline back to the control level over the next 15 min. In addition, alpha-thrombin treatment resulted in an immediate rise in DAG mass levels in the nuclear fractions. Kinetic analysis indicated that a maximum increase in DAG levels occurred 2.5-5 min after the addition of alpha-thrombin and remained elevated for at least 30 min. In cells labeled with [3H]myristic acid, alpha-thrombin treatment induced an increase in radiolabeled nuclear diglycerides, suggesting that the stimulated nuclear DAGs are derived, at least in part, from phosphatidylcholine. Our results suggest that increases in both nuclear DAG levels and PKC activity following alpha-thrombin treatment may play a role in mediating thrombin-induced nuclear responses such as changes in gene expression and cellular proliferation.

Animals↗
PubMed1992

Formyl peptide stimulates and ATP gamma S potentiates [3H]cytidine 5'-diphosphate diglyceride accumulation in human neutrophils.

Although it is evident that the chemotactic peptide FMLP activates O2-formation in neutrophils via the phosphoinositidase-mediated second messenger system, it is less clear how endogenous priming agents such as ATP and platelet activating factor potentiate FMLP action. In our study, we have examined the possible effects of the stable ATP analog adenosine 5'-O-[3-thiotriphosphate] (ATP gamma S) on cellular levels of inositol 1,4,5-trisphosphate, [Ca2+]i and diglyceride (DG), in resting and in FMLP-stimulated neutrophils. Although all three measures were increased in the presence of FMLP, only the increase in DG was enhanced by pretreatment (priming) with ATP gamma S. We also measured the accumulation of the phosphoinositide cycle intermediate cytidine 5'-diphosphate (CDP)-DG to assess possible effects of priming on phosphoinositide resynthesis. The addition of FMLP to [3H]cytidine-prelabeled neutrophils elicited an increase in the accumulation of [3H]CDP-DG that was maximally enhanced in cells that were pretreated with cytochalasin B. The stimulated accumulation of [3H]CDP-DG was completely reversed by the addition of myo-inositol. Treatment of [3H]cytidine-prelabeled neutrophils with ATP gamma S (10-100 microM) resulted in a dose-dependent synergistic increase in FMLP-stimulated [3H]CDP-DG accumulation, whereas ATP gamma S alone had no effect. The observed increases in DG and in [3H]CDP-DG, in contrast to inositol 1,4,5-trisphosphate and [Ca2+]i responses, correlates well with the ATP gamma S-priming of FMLP-induced O2-formation. A similar potentiation of FMLP-induced stimulation of CDP-DG formation was also observed with platelet-activating factor. It is proposed that the priming of FMLP responses in neutrophils proceeds via a mechanism that selectively enhances DG production through a mechanism that is independent of FMLP-induced breakdown of phosphatidylinositol bisphosphate.

Adenosine Triphosphate↗
PubMed1990

Urokinase secretion from human colon carcinomas induced by endogenous diglycerides.

Colon tumor cells are more responsive to certain growth modulators in their local environment in vivo than are normal colonocytes. Examples of this class of compounds are the fecal diglycerides (DGs)(E. Friedman et al., Cancer Res., 49: 544-548, 1989), which may act as endogenous tumor promoters. At the concentration found in vivo, fecal DGs composed of oleic, myristic, and palmitic fatty acids induced mitogenesis of all classes of benign tumor cells and of half of the resected carcinomas tested in primary culture, but induced no detectable mitogenesis of normal colonocytes. Colon tumor cells also exhibit selective responses to these endogenous modulators as measured by another biological parameter, secretion of urokinase from carcinomas than from normal colonocytes. Fecal DGs also induced a 13-fold increase in urokinase mRNA synthesis in colon carcinoma cells and induced secretion of active urokinase from each of five resected carcinomas. Colon carcinomas, at both the primary site and metastatic to the liver, secreted the Mr 55,000 form of urokinase constitutively and secreted the same form upon treatment with fecal DGs. An increase in the steady-state level of urokinase secretion by saturated-chain DGs exhibited a strong dependency on the chain length of the fatty acid residues, those of 14 and 16 carbons having the greatest activity. Thus, fecal DGs composed of oleic, myristic, and palmitic acid residues induce two biological activities selectively in colon tumor cells, each of which would enhance tumor development. Selective mitogenesis would increase adenoma and carcinoma cell number relative to normal colonocyte number, and induction of the proteolytic enzyme urokinase would aid local invasion of the carcinoma within the bowel wall.

Blotting, Western↗