Готові списки джерел за темами / Sphingosine kinases

Добірка наукової літератури з теми "Sphingosine kinases"

Автор: Grafiati
Опубліковано: 10 грудня 2022
Оновлено: 28 січня 2023

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Статті в журналах з теми "Sphingosine kinases"

1

MYu, Pushkareva, A. Bielawska, D. Menaldiv, D. Liotta, and Y. A. Hannun. "Regulation of sphingosine-activated protein kinases: selectivity of activation by sphingoid bases and inhibition by non-esterified fatty acids." Biochemical Journal 294, no. 3 (September 15, 1993): 699–703. http://dx.doi.org/10.1042/bj2940699.

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Sphingosine has been shown to activate protein kinases in Jurkat T cell cytosol [Pushkareva, Khan, Alessenko, Sahyoun and Hannun (1992) J. Biol. Chem. 267, 15246-15251]. In this study, two sphingosine-activated protein kinases were distinguished by their substrate specificity, their dose-response to sphingosine and the specificity of their activation by sphingosine and dihydrosphingosine stereoisomers. A p32-sphingosine-activated protein kinase responded to low concentrations of D-erythrosphingosine with an initial activation observed at 2.5 microM and a peak activity at 10-20 microM. This kinase showed a modest specificity for D-erythro-sphingosine over other sphingosine stereoisomers, and a preference for sphingosines over dihydrosphingosines. Phosphorylation of a p18 substrate required higher concentrations of sphingosine (20-100 microM) and showed a significant preference for the erythro isomers of sphingosine and dihydrosphingosine over the threo isomers. The ability of other lipids to modulate sphingosine activation of these kinases was also examined. Oleic acid, but not oleic alcohol or the methyl ester, induced the phosphorylation of a distinct set of substrates (probably through the activation of protein kinase C), and inhibited sphingosine-induced phosphorylation with an IC50 of approximately 20 microM. Oleic anhydride failed to induce changes in basal protein phosphorylation but inhibited sphingosine-activated protein kinases, thus distinguishing the effects of fatty acids on protein kinase C from the inhibition of sphingosine-induced phosphorylation. These studies define two distinct sphingosine-activated protein kinases and reveal an important interaction between two classes of putative lipid second messengers.
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2

Santos, Webster L., and Kevin R. Lynch. "Drugging Sphingosine Kinases." ACS Chemical Biology 10, no. 1 (November 19, 2014): 225–33. http://dx.doi.org/10.1021/cb5008426.

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3

Porter, Hunter, Hui Qi, Nicole Prabhu, Richard Grambergs, Joel McRae, Blake Hopiavuori, and Nawajes Mandal. "Characterizing Sphingosine Kinases and Sphingosine 1-Phosphate Receptors in the Mammalian Eye and Retina." International Journal of Molecular Sciences 19, no. 12 (December 5, 2018): 3885. http://dx.doi.org/10.3390/ijms19123885.

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Sphingosine 1-phosphate (S1P) signaling regulates numerous biological processes including neurogenesis, inflammation and neovascularization. However, little is known about the role of S1P signaling in the eye. In this study, we characterize two sphingosine kinases (SPHK1 and SPHK2), which phosphorylate sphingosine to S1P, and three S1P receptors (S1PR1, S1PR2 and S1PR3) in mouse and rat eyes. We evaluated sphingosine kinase and S1P receptor gene expression at the mRNA level in various rat tissues and rat retinas exposed to light-damage, whole mouse eyes, specific eye structures, and in developing retinas. Furthermore, we determined the localization of sphingosine kinases and S1P receptors in whole rat eyes by immunohistochemistry. Our results unveiled unique expression profiles for both sphingosine kinases and each receptor in ocular tissues. Furthermore, these kinases and S1P receptors are expressed in mammalian retinal cells and the expression of SPHK1, S1PR2 and S1PR3 increased immediately after light damage, which suggests a function in apoptosis and/or light stress responses in the eye. These findings have numerous implications for understanding the role of S1P signaling in the mechanisms of ocular diseases such as retinal inflammatory and degenerative diseases, neovascular eye diseases, glaucoma and corneal diseases.
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4

Maceyka, Michael, Sheldon Milstien, and Sarah Spiegel. "Sphingosine kinases, sphingosine-1-phosphate and sphingolipidomics." Prostaglandins & Other Lipid Mediators 77, no. 1-4 (September 2005): 15–22. http://dx.doi.org/10.1016/j.prostaglandins.2004.09.010.

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5

Pitson, Stuart M., Paul A. B. Moretti, Julia R. Zebol, Reza Zareie, Claudia K. Derian, Andrew L. Darrow, Jenson Qi, et al. "The Nucleotide-binding Site of Human Sphingosine Kinase 1." Journal of Biological Chemistry 277, no. 51 (October 18, 2002): 49545–53. http://dx.doi.org/10.1074/jbc.m206687200.

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Анотація:
Sphingosine kinase catalyzes the formation of sphingosine 1-phosphate, a lipid second messenger that has been implicated in a number of agonist-driven cellular responses including mitogenesis, anti-apoptosis, and expression of inflammatory molecules. Despite the importance of sphingosine kinase, very little is known regarding its structure or mechanism of catalysis. Moreover, sphingosine kinase does not contain recognizable catalytic or substrate-binding sites, based on sequence motifs found in other kinases. Here we have elucidated the nucleotide-binding site of human sphingosine kinase 1 (hSK1) through a combination of site-directed mutagenesis and affinity labeling with the ATP analogue, FSBA. We have shown that Gly82of hSK1 is involved in ATP binding since mutation of this residue to alanine resulted in an enzyme with an ∼45-fold higherKm(ATP). We have also shown that Lys103is important in catalysis since an alanine substitution of this residue ablates catalytic activity. Furthermore, we have shown that this residue is covalently modified by FSBA. Our data, combined with amino acid sequence comparison, suggest a motif of SGDGX17–21K is involved in nucleotide binding in the sphingosine kinases. This motif differs in primary sequence from all previously identified nucleotide-binding sites. It does, however, share some sequence and likely structural similarity with the highly conserved glycine-rich loop, which is known to be involved in anchoring and positioning the nucleotide in the catalytic site of many protein kinases.
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6

Allende, Maria L., Teiji Sasaki, Hiromichi Kawai, Ana Olivera, Yide Mi, Gerhild van Echten-Deckert, Richard Hajdu, et al. "Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52487–92. http://dx.doi.org/10.1074/jbc.m406512200.

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Анотація:
Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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Hait, Nitai C., Carole A. Oskeritzian, Steven W. Paugh, Sheldon Milstien, and Sarah Spiegel. "Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases." Biochimica et Biophysica Acta (BBA) - Biomembranes 1758, no. 12 (December 2006): 2016–26. http://dx.doi.org/10.1016/j.bbamem.2006.08.007.

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8

Birchwood, Christine J., Julie D. Saba, Robert C. Dickson, and Kyle W. Cunningham. "Calcium Influx and Signaling in Yeast Stimulated by Intracellular Sphingosine 1-Phosphate Accumulation." Journal of Biological Chemistry 276, no. 15 (January 19, 2001): 11712–18. http://dx.doi.org/10.1074/jbc.m010221200.

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In mammalian cells, intracellular sphingosine 1-phosphate (S1P) can stimulate calcium release from intracellular organelles, resulting in the activation of downstream signaling pathways. The budding yeastSaccharomyces cerevisiaeexpresses enzymes that can synthesize and degrade S1P and related molecules, but their possible role in calcium signaling has not yet been tested. Here we examine the effects of S1P accumulation on calcium signaling using a variety of yeast mutants. Treatment of yeast cells with exogenous sphingosine stimulated Ca2+accumulation through two distinct pathways. The first pathway required the Cch1p and Mid1p subunits of a Ca2+influx channel, depended upon the function of sphingosine kinases (Lcb4p and Lcb5p), and was inhibited by the functions of S1P lyase (Dpl1p) and the S1P phosphatase (Lcb3p). The biologically inactive stereoisomer of sphingosine did not activate this Ca2+influx pathway, suggesting that the active S1P isomer specifically stimulates a calcium-signaling mechanism in yeast. The second Ca2+influx pathway stimulated by the addition of sphingosine was not stereospecific, was not dependent on the sphingosine kinases, occurred only at higher doses of added sphingosine, and therefore was likely to be nonspecific. Mutants lacking both S1P lyase and phosphatase (dpl1 lcb3double mutants) exhibited constitutively high Ca2+accumulation and signaling in the absence of added sphingosine, and these effects were dependent on the sphingosine kinases. These results show that endogenous S1P-related molecules can also trigger Ca2+accumulation and signaling. Several stimuli previously shown to evoke calcium signaling in wild-type cells were examined inlcb4 lcb5double mutants. All of the stimuli produced calcium signals independent of sphingosine kinase activity, suggesting that phosphorylated sphingoid bases might serve as messengers of calcium signaling in yeast during an unknown cellular response.
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Ding, Tiandi, HaiJiao Chen, Yan Li, Ying Li, Ying Zhi, Zhiqiang Qu, Qiang Sun, Qingqiang Yao, and Bo Liu. "Discovery of an SphK1 inhibitor: A hybrid approach involving a receptor–ligand-complex-based pharmacophore and docking-based virtual screening." Journal of Chemical Research 46, no. 2 (March 2022): 174751982210892. http://dx.doi.org/10.1177/17475198221089222.

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Анотація:
Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
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10

Min, Junxia, David Traynor, Andrew L. Stegner, Lei Zhang, Marie H. Hanigan, Hannah Alexander, and Stephen Alexander. "Sphingosine Kinase Regulates the Sensitivity of Dictyostelium discoideum Cells to the Anticancer Drug Cisplatin." Eukaryotic Cell 4, no. 1 (January 2005): 178–89. http://dx.doi.org/10.1128/ec.4.1.178-189.2005.

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ABSTRACT The drug cisplatin is widely used to treat a number of tumor types. However, resistance to the drug, which remains poorly understood, limits its usefulness. Previous work using Dictyostelium discoideum as a model for studying drug resistance showed that mutants lacking sphingosine-1-phosphate (S-1-P) lyase, the enzyme that degrades S-1-P, had increased resistance to cisplatin, whereas mutants overexpressing the enzyme were more sensitive to the drug. S-1-P is synthesized from sphingosine and ATP by the enzyme sphingosine kinase. We have identified two sphingosine kinase genes in D. discoideum—sgkA and sgkB—that are homologous to those of other species. The biochemical properties of the SgkA and SgkB enzymes suggest that they are the equivalent of the human Sphk1 and Sphk2 enzymes, respectively. Disruption of the kinases by homologous recombination (both single and double mutants) or overexpression of the sgkA gene resulted in altered growth rates and altered response to cisplatin. The null mutants showed increased sensitivity to cisplatin, whereas mutants overexpressing the sphingosine kinase resulted in increased resistance compared to the parental cells. The results indicate that both the SgkA and the SgkB enzymes function in regulating cisplatin sensitivity. The increase in sensitivity of the sphingosine kinase-null mutants was reversed by the addition of S-1-P, and the increased resistance of the sphingosine kinase overexpressor mutant was reversed by the inhibitor N,N-dimethylsphingosine. Parallel changes in sensitivity of the null mutants are seen with the platinum-based drug carboplatin but not with doxorubicin, 5-fluorouracil, and etoposide. This pattern of specificity is similar to that observed with the S-1-P lyase mutants and should be useful in designing therapeutic schemes involving more than one drug. This study identifies the sphingosine kinases as new drug targets for modulating the sensitivity to platinum-based drugs.
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Більше джерел

Дисертації з теми "Sphingosine kinases"

1

Megidish, Tamar. "Sphingosine as second messenger, sphingosine dependent protein kinases and their substrates /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/9285.

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2

Tonelli, Francesca R. "Sphingosine kinases : evaluation of therapeutic potential using prostate cancer cell models." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18199.

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Анотація:
Sphingosine kinase 1 and 2 (SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. Alterations in SK1 function have been implicated in human prostate cancer, being involved in the acquisition of therapy resistance and progression to androgen independence, two major issues in the clinical management of this disease. This study investigated the effect of down-regulating SK1 in androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI) prostate cancer cells. The SK1 inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi) activates the proteasome by acutely inhibiting SK1 activity. Consequently, SKi induces the proteasomal degradation of SK1 isoforms, SK1a and SK1b, in LNCaP cells, which is associated with the accumulation of the pro-apoptotic lipid C22:0 ceramide and the induction of apoptosis. In contrast, SK1b is resistant to SKi-induced proteasomal degradation in LNCaP-AI cells, and this is associated with the failure to elevate ceramide le vels and to induce apoptosis. However, a different SK1 inhibitor, (S)-FTY720 vinylphosphonate overcomes this resistance to induce the proteasomal degradation of both SK1a and SK1b in LNCaP-AI cells, resulting in C16:0 ceramide accumulation and activation of apoptosis. The analysis of the effects of a selective inhibitor of SK2 revealed that SK1 and SK2 might regulate distinct functional pools of sphingolipids in prostate cancer cells. Additionally, SK1 inhibitors markedly reduce androgen receptor (AR) expression in prostate cancer cells. In particular, SKi down-regulates AR via a reactive oxygen species-dependent mechanism. Indeed, SKi treatment induces a pronounced oxidative stress response in LNCaP and LNCaP-AI cells. Thus, this study highlights a significant role of SK1 in promoting androgen receptor-dependent signalling and maintaining the survival of prostate cancer cells. This study also provides the first documented evidence of increased stability of SK1b compared with SK1a, which is associated with resistance to apoptosis. Taken together, these findings provide useful information regarding SK1-targeted therapeutic intervention for the treatment of (prostate) cancer.
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3

Bonhoure, Elisabeth. "Rôle de la sphingosine kinase-1 dans la réponse des cellules tumorales à la chimiothérapie." Toulouse 3, 2007. http://www.theses.fr/2007TOU30114.

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4

Dayon, Audrey. "Rôle de la sphingosine kinase-1 dans la survie et la progression des cellules tumorales prostatiques LNCaP vers l'androgéno-indépendance." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/307/.

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Анотація:
Le traitement du cancer de la prostate est basé sur la privation androgénique dont l'efficacité n'est que temporaire jusqu'à l'acquisition de l'androgéno-indépendace tumorale. Notre équipe a montré que l'oncogène sphingosine kinase (SK) est surexprimé dans le tissu tumoral prostatique, et que son activité enzymatique augmente avec l'agressivité tumorale. Nous avons exploré le rôle potentiel de la SK dans la survie et la progression des cellules tumorales prostatiques LNCaP vers l'androgéno-indépendance. Premièrement, nous montrons in vitro et in vivo que la privation androgénique entraîne une inhibition de l'activité SK qui est corrélée à une diminution de la prolifération cellulaire. Cette perte des capacités prolifératives peut être surmonté par la surexpression du gène codant pour la SK. L'addition de dihydrotestostérone (DHT) stimule l'activité SK et permet de ré-induire la prolifération cellulaire. Par ailleurs, l'inhibition pharmacologique de la SK bloque les effets prolifératifs de la DHT. Deuxièmement, nous démontrons l'implication de la SK dans la progression des cellules LNCaP vers le statut androgéno-indépendant. Lors de la privation androgénique prolongée nous observons une augmentation de l'activité et de l'expression protéique de la SK associées à la transdifférenciation neuroendocrine des cellules. Ces travaux impliquant la SK dans la transition vers l'androgéno-indépendance suggèrent que l'inhibition pharmacologique de la SK pourrait représenter une stratégie viable pour prévenir ou retarder la progression vers l'androgéno-indépendance
As prostate cancer cell proliferation is regulated by androgens, strategies aimed at reducing the production of androgens and/or effects are the standard of care in the management of patients with recurrent or advanced disease. Unfortunately all patients become resistant to hormonal manipulation and it is not clear how prostate cancer cells make the transition from being androgen-dependent to being androgen-independent after hormone ablation therapy. We have shown in the Lab that the oncogenic sphingosine kinase (SK) is overexpressed in tumor samples from prostate cancer patients (as compared with normal counterparts). We provide the first evidence that androgen privation induces a differential effect on SK activity in the hormono-sensitive LNCaP prostate cancer cell model. Short-term androgen removal induced a rapid and transient SK inhibition in vitro and in vivo in an orthotopically LNCaP model established in SCID mice. Conversely, long-term removal of androgen resulted in a progressive increase in SK expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SK activity. These results suggest that SK activation upon chronic androgen privation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer
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5

Niaudet, Colin. "Caractérisation et modulation des évènements initiaux contrôlant la mort radioinduite de l'endothélium microvasculaire." Nantes, 2009. https://archive.bu.univ-nantes.fr/pollux/show/show?id=34ca7579-91aa-46a5-bc5a-1291a772a1b6.

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Une irradiation unique à forte dose déclenche l'apoptose du compartiment microvasculaire via le couple sphingomyélinase acide/céramide, contrôlant l'ensemble du processus de destruction tissulaire. Nous avons étudié la connexion entre cette apoptose contrôlée par l'ASMase et la capacité largement démontrée du céramide à induire la coalescence des microdomaines membranaires en larges plateformes. L'irradiation induit simultanément la voie de mort p38, dont l'inhibition protège partiellement les cellules endothéliales de la mort radioinduite. Enfin, la désorganisation des rafts par un agent dépléteur du cholestérol entrave l'activation de p38 et la mort des cellules microvasculaires qui en résulte. Ces résultats suggèrent l'existence d'un mécanisme de mort émanant de la membrane spécifique aux cellules endothéliales irradiées, dans lequel la coalescence des rafts mène à l'activation de la voie de mort p38. Nous avons ensuite utilisé la sphingosine-1-phosphate (S1P), un antagoniste du céramide, pour moduler cette vague précoce de mort radioinduite dans l'endothélium. Nous avons validé l'usage de la S1P comme agent systémique capable de limiter les défaillances aigues survenant dans les organes suite à l'exposition à des stress sévères : l'injection de S1P abolit l'effondrement de l'endothélium et ainsi empêche la survenue du syndrome gastro-intestinal à 15 Gy, tout comme le choc septique induit par le LPS, un autre syndrome contrôlé par l'apoptose microvasculaire. Cette protection exercée par la S1P sur l'endothélium présente une double spécificité : les sphingolipides apparentés sont incapables d'induire un niveau de protection équivalent de l'endothélium, et l'effet pro-survie de la S1P est dirigé uniquement vers l'endothélium et non vers les cellules épithéliales intestinales ou les lymphocytes. L'effet protecteur de la S1P est médié par les récepteurs couplés aux protéines G, puis les protéines pro-survie Akt, comme le prouvent l'inhibition de ces deux types de molécules qui, in vivo comme in vitro, supprime l'action de la S1P
High dose of ionizing radiation drives microvascular compartment to apoptosis, which controls the whole tissue damaging-process, through the acid sphingomyelinase (ASM)/ceramide pathway. We adressed the connection between ASMase-induced apoptosis and the well-known capacity of ceramide to induce rafts microdomains coalescence into large platforms. Concomitantly to membrane remodeling, irradiation activated p38 death pathway and its blockade partially protected endothelial cells from radiation-induced death. Finally, disorganization of rafts by cholesterol-depletor hindered the p38 activation and the subsequent death-induced microvascular cells. These results suggest a specific membrane controled death mechanism in irradiated endothelial cells, where rafts coalescence leads to p38 activation and apoptosis. We then used sphingosine-1-phosphate (S1P), a ceramide antagonist, to modulate this early wave of radioinduced death in endothelium. We validated the pharmacological use of systemic S1P to restrain acute organ failure in response to severe stress: S1P injection abolished endothelial cells collapse and therefore prevented 15 Gy-induced gastrointestinal syndrome, as well as LPS-induced septic shock, another syndrome driven by microvascular apoptosis. This protection from S1P toward endothelium showed a dual specificity: related sphingolipids failed to offer the same protective effects, and this protection affected only endothelial cells as compared to intestinal epithelial cells or lymphocytes. S1P-induced protective effect is mediated through G-protein coupled receptor then the prosurvival protein Akt, as inhibition of both pathways suppresses the S1P action in vitro and in vivo
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6

Gomez-Brouchet, Anne. "Rôle de la Sphingosine Kinase 1 (SphK1) dans la régulation de la survie des cellules de neuroblastome exposées au peptide Béta-amyloïde." Toulouse 3, 2007. http://www.theses.fr/2007TOU30251.

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La démence de type Alzheimer pose un grand problème de santé publique dans les pays industrialisés et touche en France 850 000 personnes (5 % chez les plus de 65 ans et 20 % chez les plus de 85 ans). Elles se caractérise par la présence de lésions histologiques caractéristiques : les plaques séniles (PS) et les dégénérescences neurofibrillaires (DNF). L'analyse moléculaire et spatiotemporelle de ces deux lésions élémentaires a permis de mieux préciser la cascade des dysfonctionnements moléculaires et cellulaires de la maladie au cours de ces dernières années. Des travaux récents ont impliqué la voie Sphingomyéline/Céramide dans la mort neuronale induite par le peptide Aβ et donc dans la pathogénie de la maladie d'Alzheimer. En l'espace d'une décennie, les métabolites sphingolipidiques, c'est-à-dire céramide, sphingosine et sphingosine 1-phosphate (S1P), ont émergé comme les représentants d'une nouvelle classe de seconds messagers lipidiques régulant la prolifération, la différenciation et l'apoptose. Le céramide induit des réponses antiprolifératives et proapoptotiques, alors que l'addition de S1P favorise la survie cellulaire. Les effets opposés de ces deux sphingolipides ont conduit au concept selon lequel la balance dynamique entre les taux de céramide et de S1P représente un facteur déterminant pour le devenir de la cellule. Un acteur majeur de cette balance est la sphingosine kinase-1 (SphK1), responsable de la production de S1P. Compte tenu de ces données, nous avons étudié le rôle de la sphingosine kinase (SphK1) dans la régulation des signaux de survie et de mort des cellules humaines de neuroblastome SHSY5Y sous l'action du peptide Aβ 25-35. Il ressort de nos travaux que la SphK1 régule la survie de cellules de neuroblastome exposées au peptide β-amyloïde (25-35). En effet, l'activité SphK1 est fortement inhibée en réponse au traitement par le peptide β-amyloïde (25-35) via un mécanisme redox dépendant. .
Alzheimer disease (AD) is a critical problem of public health in the industrialized countries. AD affects 24. 3 million individuals in the world. In France, the number of AD patients represents 5 % of the population over 65 years-old (20 % of people over 85 years-old). Important progress have been made during the last ten years: Mutations were characterized, as well as genetic or environmental risk factors. A better analysis of the two elementary lesions of AD in their distribution and molecular characterization has allowed a better comprehension of the disease. Thus, the description of a dysfunction of proteins APP (Amyloid Precursor Protein) and Tau in sporadic and familial AD has led to therapeutic experiments and tests on cellular or animal models with promising results. Even though the diagnosis of AD still remains related to the neuropathology, it is evoked more precociously due to the progress in neuropsychological evaluation and imaging procedures. The advances in the comprehension of the disease mechanisms should make possible the discovery of new therapeutic targets. .
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Thompson, Dawn. "Sphingosine kinase and sphingosine-1 phosphate phosphatase : molecular tools to investigate the role of sphingosine-1-phosphate." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401320.

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Congdon, Molly D. "Structure Activity Relationship Studies on Isoform Selective Sphingosine Kinase Inhibitors." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/82129.

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A variety of diseases including Alzheimer's disease, asthma, cancer, fibrosis, multiple sclerosis, and sickle cell disease have been associated with elevated levels of sphingosine-1-phosphate (S1P). S1P, a pleiotropic lipid mediator involved in a broad range of cellular processes, is synthesized solely by the phosphorylation of sphingosine (Sph) and is catalyzed by the two isoforms of sphingosine kinase (SphK1 and SphK2). Therefore, SphKs are a potential therapeutic target; however, the physiological role of SphK2 is still emerging. In order to determine the role of SphK2 in vivo, more potent and selective small molecule inhibitors of SphK2, as well as dual inhibitors are necessary. Herein, explorations and advancements on the second generation SphK2 selective inhibitor SLR080811 are disclosed. Investigations into the lipophilic tail region of the hSphK2 inhibitor SLR080811 are detailed. This investigation highlights the dependency of SphK2 selectivity and potency on overall compound length. More importantly, this study identified the internal aryl ring of SLR080811 as a key pharmacophore of the scaffold. To further probe the significance of the aromatic region, the phenyl ring was replaced by a 2,6-naphthyl ether skeleton. Investigations into the tail region of this scaffold are described in detail. Key discoveries from this structure-activity relationship study include SLC5111312 (hSphK2 Ki = 0.90 μM, dual hSphK inhibitor), SLC5091592 (hSphK2 Ki = 1.02 μM, > 20-fold hSphK2 selective) and SLC5121591 (hSphK2 Ki = 0.61 μM, >16-fold hSphK2 selective). Molecular modeling studies with hSphK2 indicate that the extended aromatic group is able to participate in π-π stacking interactions with Phe548. In silico docking studies indicate that a guanidine hydrogen bond to Asp211 is key for SphK2 selectivity, and incorporation of a 3'-hydroxyl group on the pyrrolidine ring increases hydrogen bonding to Asp308, thereby increasing SphK1 potency and reducing selectivity. Additionally, biological studies employing SLC5111312 have helped to further elucidate the role of SphK2, suggesting that SphK2 has a catalytic role in the regulation of blood S1P levels. The shape of the hSphK2 binding pocket was probed by introducing an indole moiety in place of the naphthyl ring and varying its substitution pattern. One key discovery from this study is SLC5101465 (hSphK2 Ki = 0.09 μM, > 111 fold SphK2 selective), which has a 1,5-indole substitution pattern with an N-nonyl "tail". Molecular docking simulations highlight the importance of rotatable bonds and a relatively linear orientation between the "head group" and "tail group" to maintain essential hydrogen bond interactions to Asp residues with the guanidine moiety while minimizing steric interactions in the middle of the binding pocket. Expanding upon the 1,5-indole scaffold of SLC5101465, a series of aryl tail derivatives are examined. This study confirms the necessity of electron withdrawing groups located at the end of the inhibitor scaffold to optimize binding in the tail region of the SphK2 binding pocket.
Ph. D.
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9

Ng, Carl Khee-Yew. "Drought induced guard cell signal transduction involves sphingosine 1 phosphate." Thesis, Lancaster University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250627.

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Andrieu, Guillaume. "Rôle de la voie sphingosine kinase/sphingosine 1-phosphate dans le contrôle de la division cellulaire." Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2605/.

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La division cellulaire est cruciale pour le maintien de la stabilité du génome. Or, les gènes régulateurs de la mitose sont fréquemment mutés dans le cancer. Les cellules cancéreuses possèdent généralement un nombre anormal de chromosomes et la majorité des tumeurs solides sont aneuploïdes. Cette caractéristique favorise notamment l'initiation et la progression tumorale mais constitue également un facteur de mauvais pronostic et de résistance thérapeutique. La voie sphingosine kinases/sphingosine 1-phosphate (SphKs/S1P) régule la prolifération et la survie cellulaire, l'apoptose, la migration ou encore la réponse inflammatoire. De nombreuses études ont montré que sa surexpression favorise l'initiation et la progression tumorale mais également l'invasion, le processus métastatique et l'acquisition de résistance à la thérapie. Mon projet de thèse vise à mettre à évidence le rôle de la voie SphKs/S1P dans la régulation de la mitose et de la ségrégation chromosomique. Nos résultats montrent pour la première fois que les SphKs contrôlent la progression mitotique. Cette régulation implique la production de S1P et son interaction avec son récepteur couplé aux protéines G, le S1P5. La surexpression des SphKs ou la surproduction de S1P altèrent la ségrégation des chromosomes. De plus, nos données récentes suggèrent que la voie SphKs/S1P puisse être impliquée dans l'acquisition de résistance aux agents de chimiothérapie ciblant la mitose. Nous montrons pour la première fois que la voie SphKs/S1P est un nouveau régulateur de la mitose. Ces travaux permettent de mieux comprendre comment la voie SphKs/S1P contribue au développement tumoral et renforcent leur intérêt comme cible thérapeutique dans le traitement du cancer
Cell division is a crucial process for genome maintenance. In cancer, numerous regulators of mitosis are mutated or altered, impeding the quality of chromosome segregation. Tumors exhibit a high chromosomal instability and are frequently aneuploid. These hallmarks promote tumor initiation and progression but are also associated with poor prognosis and therapeutic resistance. The sphingosine kinases/sphingosine 1-phosphate (SphKs/S1P) pathway is a key regulator of several fundamental biological processes including cell proliferation, survival, apoptosis, migration or inflammatory response. Numerous studies have shown that the up-regulation of the SphKs/S1P pathway promotes tumor initiation and progression, invasion, metastasis and resistance to anticancer therapies. We are interested in the role of the SphKs/S1P pathway in cell division regulation. Our data indicate for the first time that SphKs regulate mitotic progression trough S1P production and the interaction with its G protein-coupled receptor S1P5. Furthermore, we showed that the up-regulation of the SphKs/S1P pathway impairs chromosome segregation. Finally, our recent data suggest that the SphKs/S1P pathway may be involved in the acquisition of resistance to mitotic chemotherapeutic agents. Overall, we have identified the SphKs/S1P/S1P5 pathway as a new genuine regulator of mitosis. We give support to the understanding of the implication of the SphKs/S1P pathway in tumoral progression and strengthen its interest as anti-cancer therapeutic targets
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Частини книг з теми "Sphingosine kinases"

1

Pyne, Susan, David R. Adams, and Nigel J. Pyne. "Sphingosine Kinases as Druggable Targets." In Lipid Signaling in Human Diseases, 49–76. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/164_2018_96.

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2

Pitman, Melissa R., Kate E. Jarman, Tamara M. Leclercq, Duyen H. Pham, and Stuart M. Pitson. "Sphingosine Kinases: Biochemistry, Regulation, and Roles." In Lysophospholipid Receptors, 153–83. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2013. http://dx.doi.org/10.1002/9781118531426.ch9.

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3

Meng, H., and V. M. Lee. "Widespread Expression of Sphingosine Kinases and Sphingosine 1-Phosphate (S1P) Lyase Suggests Diverse Functions in the Vertebrate Nervous System." In Lysophospholipid Receptors, 419–32. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2013. http://dx.doi.org/10.1002/9781118531426.ch19.

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4

Olivera, Ana, and Sarah Spiegel. "Sphingosine Kinase." In Phospholipid Signaling Protocols, 233–42. Totowa, NJ: Humana Press, 1998. http://dx.doi.org/10.1385/0-89603-491-7:233.

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5

Neubauer, Heidi, and Stuart Pitson. "Sphingosine Kinase 2 (SPHK2)." In Encyclopedia of Signaling Molecules, 5119–28. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101836.

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Neubauer, Heidi, and Stuart Pitson. "Sphingosine Kinase 2 (SPHK2)." In Encyclopedia of Signaling Molecules, 1–9. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101836-1.

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7

Maceyka, Michael, Sergio E. Alvarez, Sheldon Milstien, and Sarah Spiegel. "Activation of Sphingosine Kinase 1." In Sphingolipid Biology, 197–206. Tokyo: Springer Japan, 2006. http://dx.doi.org/10.1007/4-431-34200-1_14.

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8

Gandy, K. Alexa Orr, and Lina M. Obeid. "Regulation of the Sphingosine Kinase/Sphingosine 1-Phosphate Pathway." In Sphingolipids in Disease, 275–303. Vienna: Springer Vienna, 2013. http://dx.doi.org/10.1007/978-3-7091-1511-4_14.

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9

Brizuela, Leyre, and Olivier Cuvillier. "Biochemical Methods for Quantifying Sphingolipids: Ceramide, Sphingosine, Sphingosine Kinase-1 Activity, and Sphingosine-1-Phosphate." In Methods in Molecular Biology, 1–20. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-61779-800-9_1.

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10

Selvam, Shanmugam Panneer, and Besim Ogretmen. "Sphingosine Kinase/Sphingosine 1-Phosphate Signaling in Cancer Therapeutics and Drug Resistance." In Sphingolipids in Disease, 3–27. Vienna: Springer Vienna, 2013. http://dx.doi.org/10.1007/978-3-7091-1511-4_1.

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Тези доповідей конференцій з теми "Sphingosine kinases"

1

Gairhe, Salina, Masahiko Oka, and Ivan McMurtry. "Pulmonary Arterial Expression Of Sphingosine Kinases Is Markedly Increased In Pulmonary Arterial Hypertension." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4752.

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2

Gairhe, Salina, Abdallah Alzoubi, Michie Toba, Masahiko Oka, and Ivan McMurtry. "Effect Of Dehydroepiandrosterone On The Expression Of Sphingosine Kinases In Pulmonary Arteries Of Sugen Hypoxia Rat Model Of Pulmonary Arterial Hypertension." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4777.

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3

Ghent, Matthew V., Youngleem Kim, Ana Jakimenko, and C. Patrick Reynolds. "Abstract 5262: Resistance to fenretinide in neuroblastoma is associated with increased expression of sphingosine kinase and sphingosine-1-phosphate receptors and targeting sphingosine kinase reverses resistance." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-5262.

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4

Timmons, Sheila, and Jack Hawiger. "REGULATION OF PLATELET RECEPTORS FOR FIBRINOGEN AND VON WILLEBRAND FACTOR BY PROTEIN KINASE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644674.

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Positive and negative regulation of platelet receptors for adhesive proteins, fibrinogen (F) and von Willebrand Factor (vWF) determines whether binding of these ligands will or will not take place. We have shown previously that ADP stimulates and cyclic AMP inhibits binding of F and vWF to human platelets. Now we show that positive regulation of F and vWF binding to platelets via the glycoprotein 11b/1111a complex is dependent on platelet Protein Kinase C, a calcium- and phospholipid-dependent enzyme. A potent activator of Protein Kinase C, phorbol-12-myristoyl-13-acetate (PMA) induced saturable and specific binding of F and vWF which was inhibited by synthetic peptides, gamma chain .dodecapeptide (gamma 400-411) and RGDS. The phosphorylation of 47kDa protein (P47), a marker of Protein Kinase C activation in platelets, preceded binding of F and vWF induced with PMA as well as with ADP and thrombin. Sphingosine, an inhibitor of Protein Kinase C, blocked binding of F and vWF to platelets stimulated with PMA, ADP, and thrombin. Inhibition of binding was concentration-dependent and it was accompanied by inhibition of platelet aggregation. Thus, stimulation of Protein Kinase C is required for exposure of platelet receptors for adhesive proteins whereas inhibition of Protein Kinase C prevents receptorexposure. Protein Kinase C fulfills the role of an intraplatelet signal transducer, regulating receptors for adhesive proteins, and constitutes a target for pharmacologic modulation of the adhesive interactions of platelets.
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Roviezzo, Fiorentina, Giovanna De Cunto, Maria Antonietta Riemma, Ida Cerqua, Monica Luccattelli, and Giuseppe Cirino. "Sphingosine kinase/sphingosine-1-phosphate pathway contributes to airway hyper-responsiveness in cigarette smoke exposed mice." In Abstracts from the 17th ERS Lung Science Conference: ‘Mechanisms of Acute Exacerbation of Respiratory Disease’. European Respiratory Society, 2019. http://dx.doi.org/10.1183/23120541.lungscienceconference-2019.pp116.

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6

Gao, Peng, Yan Zhuang, and Charles D. Smith. "Abstract 838A: Characterization of sphingosine kinase isoenzyme selective inhibitors." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-838a.

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7

Gutbier, Birgitt, Stefanie M. Schoenrock, Rainer Haberberger, Andreas C. Hocke, Stefan Hippenstiel, Anja Luth, Burkhard Kleuser, et al. "Sphingosine Kinase-1 And Sphingosine-1-Phosphate Promote The Development Of Acute Lung Injury In Pneumoccocal Pneumonia." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1040.

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Gorshkova, I., E. Berdyshev, P. Usatyuk, S. Kalari, Y. Zhao, NG Pyne, S. Pyne, and V. Natarajan. "Involvement of Intracellular Sphingosine-1-Phosphate in Lung Endothelial Cell Motility: Role of Sphingosine Kinase 1, Sphingosine-1-Phosphate Lyase and Serine Palmitoyl Transferase." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6121.

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Kawamori, Toshihiko, Hideki Furuya, Masayuki Wada, Jacek Bielawski, Yusuf A. Hannun, and Lina M. Obeid. "Abstract B80: Role for sphingosine kinase 1 in colon carcinogenesis." In Abstracts: AACR International Conference on Frontiers in Cancer Prevention Research‐‐ Dec 6–9, 2009; Houston, TX. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1940-6207.prev-09-b80.

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Wadgaonkar, S., O. Ramadan, N. Grinkina, S. Puttaswamy, and R. Wadgaonkar. "Functional Interaction of Lyn-Sphingosine Kinase in Endothelial Cell Microdomains." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6118.

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Звіти організацій з теми "Sphingosine kinases"

1

Maceyka, Michael W. Regulation of Sphingosine Kinase in Prostate Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, March 2004. http://dx.doi.org/10.21236/ada427918.

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2

Maceyka, Michael W. Regulation of Sphingosine Kinase in Prostate Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, March 2003. http://dx.doi.org/10.21236/ada420163.

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3

Hobson, John P. Regulation of Cell Survival in Human Breast Cancer Cells by Sphingosine Kinase. Fort Belvoir, VA: Defense Technical Information Center, January 2001. http://dx.doi.org/10.21236/ada393851.

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4

Sankala, Heidi, and Sarah Spiegel. The Role of Sphingosine Kinase 2 in Apoptosis of Human Breast Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, May 2006. http://dx.doi.org/10.21236/ada455788.

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