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Functional roles of sphingosine, sphingosine-1-phosphate, and methylsphingosines: in regard to membrane sphingolipid signaling pathways
, 1997
"... The signaling roles of ceramide and sphingosine produced through the degrading processes of membrane sphingolipids are currently receiving hot attention in the biochemical and biomedical research fields. For these 9 years at the Biomembrane Institute in Seattle, we have studied functional roles of v ..."
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The signaling roles of ceramide and sphingosine produced through the degrading processes of membrane sphingolipids are currently receiving hot attention in the biochemical and biomedical research fields. For these 9 years at the Biomembrane Institute in Seattle, we have studied functional roles of various sphingolipids such as ceramide, sphingosine, methylsphingosines, and sphingosine 1-phosphate in a variety of biomedical systems. In this article, first, the recent conceptual developments on sphingolipid signaling pathways is outlined. Next, our recent findings on the functional roles of sphingolipids are described focusing on (i) functional roles of sphingosine 1-phosphate in cell motility regulation and platelet activation (ii) involvement of sphingosine in cell signaling (iii) effects of methyl-sphingosines in cancer cell apoptosis induction and in the regulation of inflammatory processes. Based upon these findings from our studies and others, the perspective of future sphingosine research (sphingology or sphingophysiology) is briefly discussed.
Ceramide-b-D-Glucuronide: Synthesis, Digestion, and Suppression of Early Markers
"... Dietary sphingolipids inhibit chemically induced colon cancer in mice. The most likely mediators of this effect are the metabolites ceramide (Cer) and sphingosine, which induce growth arrest and apoptosis in trans-formed cells. Sphingolipids are digested in both the upper and the lower intestine; th ..."
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Dietary sphingolipids inhibit chemically induced colon cancer in mice. The most likely mediators of this effect are the metabolites ceramide (Cer) and sphingosine, which induce growth arrest and apoptosis in trans-formed cells. Sphingolipids are digested in both the upper and the lower intestine; therefore, a more colon-specific method of delivery of sphingo-lipids might be useful. A Cer analogue with a D-glucuronic acid attached at the primary hydroxyl of N-palmitoyl-D-sphingosine (Cer-b-glucuro-nide) was synthesized and evaluated as a substrate for Escherichia coli b-glucuronidase and colonic digestion, as well as for suppression of early events in colon carcinogenesis in CF1 mice treated with 1,2-dimethylhy-drazine. Purified b-glucuronidase (EC 3.2.1.31) and colonic segments (as a source of colonic enzymes and microflora) hydrolyzed Cer-b-glucuro-nide to release Cer, as analyzed by tandem mass spectrometry. More than 75 % of the Cer-b-glucuronide was cleaved in an 8-h incubation with the colonic segments. When Cer-b-glucuronide was administered for 4 weeks as 0.025 % and 0.1 % of the diet (AIN 76A) to 1,2-dimethylhydrazine-treated mice, there were significant reductions in colonic cell proliferation, as determined by in vivo BrdUrd incorporation, and in the appearance of aberrant crypt foci. The effect of dietary Cer-b-glucuronide on aberrant crypt foci correlated significantly with the length of the colon, which suggests that Cer-b-glucuronide was most effective when there was a larger compartment for digestion. Thus, synthetic sphingolipids that tar-get the colon for the release of the bioactive backbones offer a promising approach to colon cancer prevention.
Induction of apoptosis using sphingolipids activates a chloride current in Xenopus laevis oocytes
, 1999
"... apoptosis using sphingolipids activates a chloride current in Xenopus laevis oocytes. Am J Physiol Cell Physiol 279: C158–C165, 2000.—The purpose of this study was to inves-tigate whether the cell shrinkage that occurs during apopto-sis could be explained by a change of the activity in ion transport ..."
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apoptosis using sphingolipids activates a chloride current in Xenopus laevis oocytes. Am J Physiol Cell Physiol 279: C158–C165, 2000.—The purpose of this study was to inves-tigate whether the cell shrinkage that occurs during apopto-sis could be explained by a change of the activity in ion transport pathways. We tested whether sphingolipids, which are potent pro-apoptotic compounds, can activate ionic cur-rents in Xenopus laevis oocytes. Apoptosis was characterized in our model by a decrease in cell volume, a loss of cell viability, and DNA cleavage. Oocytes were studied using voltage-clamp after injection with N,N-dimethyl-D-erythro-sphingosine (DMS) or D-sphingosine (DS). DMS and DS ac-tivated a fast-activating, slowly inactivating, outwardly rec-tifying current, similar to ICl-swell, a swelling-induced chloride current. Lowering the extracellular chloride dramat-
Pour obtenir Le grade de docteur Formation doctorale: Biochimie
, 2012
"... ABSTRACT.................................................................................................................. 4 ..."
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ABSTRACT.................................................................................................................. 4
JCB Article Expression of �-catenin in �-catenin–deficient cells increases resistance to sphingosine-induced apoptosis
"... �-Catenin, an intracellular protein, associates with the COOH-terminal region of cadherin cell adhesion molecules through interactions with either �-catenin or �-catenin (plakoglobin). The full activity of cadherins requires a linkage to the actin cytoskeleton mediated by catenins. We transfected �- ..."
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�-Catenin, an intracellular protein, associates with the COOH-terminal region of cadherin cell adhesion molecules through interactions with either �-catenin or �-catenin (plakoglobin). The full activity of cadherins requires a linkage to the actin cytoskeleton mediated by catenins. We transfected �-catenin–deficient colon carcinoma cells with a series of �-catenin constructs to determine that �-catenin expression increases the resistance to apoptosis induced by sphingosine. Two groups of constructs, containing deletions in either the middle segment of the molecule or the COOH terminus, induced morphological changes, cell compaction, and decreases in cell death. In �-catenin–expressing cells, inhibition of cadherin cell adhesion by treatment with anti–E-cadherin antibodies did not decrease the cells viability. �-Catenin expression partially suppressed the downregulation of Bcl-xL and the activation of caspase 3. Expression of p27kip1 protein, an inhibitor of cyclin-dependent kinases, was increased by �-catenin expression in low density cell cultures. The increased levels of p27kip1 correlated with both increased resistance to cell death and morphological changes in transfectants containing deletion mutants. Transfectionmediated upregulation of p27kip1 decreases sphingosineinduced cell death in �-catenin–deficient cells. We postulate that �-catenin mediates transduction of signals from the cadherin–catenin complex to regulate the apoptotic cascade via p27kip1.
DIFFERENTIAL CYTOTOXICITY OF LONG-CHAIN BASES FOR HUMAN ORAL KERATINOCYTES, FIBROBLASTS, DENDRITIC AND ORAL
, 2014
"... Differential cytotoxicity of long-chain bases for human oral keratinocytes, fibroblasts, dendritic and oral squamous cell carcinoma cell lines ..."
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Differential cytotoxicity of long-chain bases for human oral keratinocytes, fibroblasts, dendritic and oral squamous cell carcinoma cell lines
Kinase and a Rho-Associated Kinase-Mediated Signal Impair Expression of p21Cip1/Waf1 in Phorbol 12-Myristate-13-
, 2002
"... This article cites 71 articles, 37 of which can be accessed free ..."
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Formation of Free Sphingosine1
, 1997
"... To elucidate the physiologic role of sphingolipid-derived products as signaling molecules, we analyzed the levels of endogenous sphingosine (Sph) derivatives in human platelets. When the platelets were stimulated with thrombin or 12-O-tetradecanoylphorbol 13-ace-tate, neither ceramide formation nor ..."
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To elucidate the physiologic role of sphingolipid-derived products as signaling molecules, we analyzed the levels of endogenous sphingosine (Sph) derivatives in human platelets. When the platelets were stimulated with thrombin or 12-O-tetradecanoylphorbol 13-ace-tate, neither ceramide formation nor sphingomyelin hydrolysis was observed, which suggests that the sphingomyelin cycle may not be an essential part of the signaling pathway under these conditions. In contrast, Sph was found to increase in platelets upon stimula-tion. The level of Sph 1-phosphate, which is formed from Sph by the action of Sph kinase, was not affected under our conditions. Although it has been established that Sph inhibits protein kinase C, which regulates the functional responses of the platelets, Sph levels which exert an inhibitory effect on protein kinase C cannot be attained under physiological conditions (without exogenous Sph). Considering the stimulation of the synthesis of Sph by the physiological agonist thrombin, we speculate that Sph is a signaling molecule of physiological importance in platelets, but protein kinase C may not be its target. Key words: ceramide, platelet, protein kinase C, sphingosine, sphingosine 1-phosphate. The process of platelet activation in the circulation is highly
