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Edg-6 as a putative sphingosine 1-phosphate receptor coupling to Ca²⁺ signaling pathway

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第2期268卷 583-589页

作者： Yamazaki, Y Kon, J Sato, K Tomura, H Sato, M Yoneya, T Okazaki, H Okajima, F Ohta, H Gunma Univ Lab Signal Transduct Inst Mol & Cellular Regulat Maebashi Gumma 3718512 Japan Kirin Brewery Co Ltd Pharmaceut Res Lab Takasaki Gumma 3701295 Japan Kirin Brewery Co Ltd Cent Labs Key Technol Kanazawa Ku Yokohama Kanagawa 2360004 Japan

The endothelial differentiation gene-6 (Edg-6) was recently identified as an orphan G-protein-coupled receptor. Its predicted amino acid sequence is very close to Edg family of receptor proteins whose ligand is supposed to be lysophosphatidic acid (LPA) or lysosphingolipid such as sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), Transfection of the Edg-6 into Chinese hamster ovary (CHO) cells and K562 cells resulted in the appearance of high-affinity [H-3]SIP binding activity. Among lipids employed, S1P and, even though less potent, SPC, displaced the [H-3]S1P binding, but LPA was inactive. In Edg-6-transfected CHO cells, an increase in cytosolic Ca2+ concentration in response to S1P or SPC was clearly enhanced without change in the LPA-induced action as compared with the vector-transfected cells. The enhancement of the Ca2+ response was associated with a significant accumulation of inositol phosphate, reflecting activation of phospholipase C. Similar enhancement of Ca2+ response to S1P or SPC was also observed in Edg-6-expressing K562 cells. These lipid-induced actions in CHO cells and K562 cells expressing Edg-6 were markedly suppressed by pertussis toxin treatment. We conclude that Edg-6 is one of S1P or lysosphingolipid receptors that couple to phospholipase C-Ca2+ system through pertussis toxin-sensitive G-proteins, 2000 Academic Press.

关键词： CHO细胞钙/代谢钙信号仓鼠亚科酶激活 K562细胞溶血磷脂素类受体细胞表面/生物合成受体细胞表面/代谢受体 G-蛋白偶联受体溶血磷脂信号传导鞘氨醇/类似物和衍生物鞘氨醇/代谢动物人类

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Spectroscopic detection of endovesiculation by large unilamellar phosphatidylcholine vesicles: Effects of chlorpromazine, dibucaine, and safingol

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BIOORGANIC & MEDICINAL CHEMISTRY 1999年第7期7卷 1373-1379页

作者： Tedesco, MM Matile, S Georgetown Univ Dept Chem Washington DC 20057 USA

Endovesiculation by large unilamellar vesicles (LUVs) induced by cationic amphiphiles is described in this work. A recent procedure to monitor phagocytosis of vesicles by macrophages by determining the amount of the simultaneously internalized water-soluble fluorescent dye HPTS with external quencher was adapted to LUVs (Daleke, D. L.;Hong, K.;Papahadjopoulos, D. Biochim. Biophys. Acta 1990, 1024, 352). Compared to dibucaine and safingol, the local anesthetic chlorpromazine (CPZ) was found to be the most efficient inducer of HPTS-internalization by LUVs. Control experiments using LUVs with entrapped HPTS indicated that the observed dye-internalization does not originate from transient lysis. A strong increase in activity above the critical micelle concentration of CPZ implies the importance of CPZ-micelles for endovesiculation. The significantly less efficient CPZ-induced HPTS-internalization by LUVs with 68 nm compared to 176 nm diameter further diminishes the likelihood of a micelle/bilayer fusion mechanism and supports the presence of 'zipper-type' endovesiculation by LUVs with diameters as small as 68 nm. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：芳基磺酸盐类/代谢氯丙嗪/药理学地布卡因/药理学剂量效应关系药物胞吞作用/药物作用荧光染料/代谢脂质体/化学脂质体/药物作用脂质体/代谢磷脂酰胆碱类/化学磷脂酰胆碱类/代谢吡啶鎓化合物/化学光谱分析/方法鞘氨醇/类似物和衍生物鞘氨醇/药理学

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Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第14期97卷 7859-7864页

作者： Mandala, SM Thornton, R Galve-Roperh, I Poulton, S Peterson, C Olivera, A Bergstrom, J Kurtz, MB Spiegel, S Georgetown Univ Med Ctr Dept Biochem & Mol Biol Washington DC 20007 USA Merck Res Labs Dept Infect Dis Rahway NJ 07065 USA

Sphingosine and sphingosine-1-phosphate (SPP) are interconvertible sphingolipid metabolites with opposing effects on cell growth and apoptosis. Based on sequence homology with LBP1, a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast, we report here the cloning, identification, and characterization of a mammalian SPP phosphatase (mSPP1). This hydrophobic enzyme, which contains the type 2 lipid phosphohydrolase conserved sequence motif, shows substrate specificity for SPP. Partially purified Myc-tagged mSPP1 was also highly active at dephosphorylating SPP. When expressed in yeast, mSPP1 can partially substitute for the function of LBP1. Membrane fractions from human embryonic kidney HEK293 cells transfected with mSPP1 markedly degraded SPP but not lysophosphatidic acid, phosphatidic acid, or ceramide-1-phosphate. Enforced expression of mSPP1 in NIH 3T3 fibroblasts not only decreased SPP and enhanced ceramide levels, it also markedly diminished survival and induced the characteristic traits of apoptosis. Collectively, our results suggest that SPP phosphohydrolase may regulate the dynamic balance between sphingolipid metabolite levels in mammalian cells and consequently influence cell fate.

关键词：氨基酸序列细胞凋亡克隆分子 DNA 互补/遗传学基因表达溶血磷脂素类膜蛋白质类分子序列数据磷酸单酯水解酶类/遗传学磷酸单酯水解酶类/代谢 RNA 信使/分离和提纯酿酒酵母蛋白质类序列同源性氨基酸鞘氨醇/类似物和衍生物鞘氨醇/代谢底物特异性组织分布动物小鼠

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Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells

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EXPERIMENTAL CELL RESEARCH 1999年第2期253卷 663-672页

作者： Fujikawa, K Scherpenseel, ID Jain, SK Presman, E Varticovski, L Tufts Univ Sch Med Dept Med St Elizabeths Med Ctr Boston MA 02135 USA

Angiopoietin-1 is a unique growth factor which induces Tie2 receptor autophosphorylation and interaction with signal transduction molecules, GRB2 and p85 subunit of PI 3-kinase, but no detectable mitogenic response. Here we show that PI 3-kinase-dependent activation of Akt and attachment to extracellular matrix are required for angiopoietin-1-mediated endothelial cell survival. Apoptosis of growth factor-deprived cells grown in monolayer was decreased by angiopoietin-1 and correlated with Akt activation. In contrast, angiopoietin-1, bFGF or VEGF failed to protect cells in suspension culture. Ceramide, an intermediate of several apoptotic pathways, interferes with growth factor-mediated Akt activation. Ceramide induced endothelial cell death and abolished angiopoietin-1-mediated activation of Akt and the effect on cell survival. In addition, we found that PI 3-kinase activity is necessary for migration of endothelial cells in response to Angiopoietin-1. A transient activation of MAPK/ERKs was also detected within 10 min after stimulation with angiopoietin-1. In contrast to VEGF-mediated biological effects, inhibition of MAPK/ERKs by PD98059 in endothelial cells did not affect angiopoietin-1 mediated survival or migration. These findings indicate significant differences in intracellular signaling between VEGF and angiopoietin-1 and that PI 3-kinase lipid products are key mediators of the biological effects of angiopoietin-1. (C) 1999 Academic Press.

关键词：血管生成素1 细胞凋亡/生理学细胞黏附/生理学细胞运动/生理学细胞存活/药物作用细胞存活/生理学色酮类/药理学内皮生长因子/药理学内皮血管/细胞学内皮血管/酶学酶激活/药物作用酶激活/生理学酶抑制剂/药理学成纤维细胞生长因子2/药理学淋巴因子/药理学膜糖蛋白类/代谢丝裂原激活蛋白激酶类/代谢吗啉类/药理学蛋白质丝氨酸苏氨酸激酶/代谢原癌基因蛋白质类原癌基因蛋白质c-akt 鞘氨醇/类似物和衍生物鞘氨醇/药理学脐静脉/细胞学血管内皮生长因子A 血管内皮生长因子类人类

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Stimulation of sphingosine-1-phosphate formation by the P2Y₂ receptor in HL-60 cells:: Ca²⁺ requirement and implication in receptor-mediated Ca²⁺ mobilization, but not MAP kinase activation

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MOLECULAR PHARMACOLOGY 2000年第3期58卷 491-497页

作者： Alemany, R Sichelschmidt, B Zu Heringdorf, DM Lass, H Van Koppen, CJ Jakobs, KH Univ Essen Gesamthsch Klinikum Inst Pharmakol D-45122 Essen Germany

Sphingosine-1-phosphate (SPP), produced by sphingosine kinase, has recently been reported to act as an intracellular second messenger for Ca2+ and mitogenic responses triggered by membrane receptors and as an extracellular ligand for specific SPP receptors. Here, we investigated the signaling pathway leading to SPP production by the G protein-coupled P2Y(2) receptor and its functional implication in human leukemia (HL-60) cells, which do not respond to extracellular SPP. P2Y(2) receptor activation by UTP or ATP resulted in rapid and transient production of SPP, which was insensitive to pertussis toxin and blocked by the sphingosine kinase inhibitor, DL-threo-dihydrosphingosine. Treatment of HL-60 cells with this inhibitor did not affect activation of mitogen-activated protein kinases, but suppressed Ca2+ mobilization by the P2Y(2) receptor. However, receptor-induced SPP production apparently required an increase in intracellular Ca2+ concentration, but not Ca2+ influx, and was mimicked by exposure of cells to Ca2+ ionophores. Taken together, activation of the P2Y(2) receptor stimulates SPP production in HL-60 cells, a process apparently not required for mitogen-activated protein kinase activation, but most likely representing an amplification system for receptor-mediated Ca2+ signaling.

关键词：生物转运钙/代谢酶激活 HL-60细胞溶血磷脂素类丝裂原激活蛋白激酶类/代谢受体嘌呤能P2/代谢受体嘌呤能P2Y2 鞘氨醇/类似物和衍生物鞘氨醇/生物合成人类

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Tumor necrosis factor-α-induced apoptosis is associated with suppression of insulin-like growth factor binding protein-5 secretion in differentiating murine skeletal myoblasts

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第3期183卷 330-337页

作者： Meadows, KA Holly, JMP Stewart, CEH Univ Bristol Bristol Royal Infirm Dept Surg Bristol BS2 8HW Avon England

Wasting of muscle and fat during cachexia exceeds that explained by reduced food intake alone. This wasting may result from an imbalanced cytokine environment, which could lead to increased protein catabolism. Supporting this, tumor necrosis factor-alpha (TNF-alpha) is raised in several animal models of cachectic muscle wasting. Therefore, we assessed the effects of TNF-alpha and its second messenger, ceramide, on the proliferation, differentiation, and survival of murine C2 skeletal myoblasts. Because insulin-like growth factor binding protein-5 (IGFBP-5) and insulin-like growth factor-II (IGF-II) are potent regulators of myoblast proliferation and differentiation, we monitored the ability of exogenous TNF-alpha to manipulate this system. Fibroblast growth factor (FGF) ceramide, or TNF-alpha suppressed differentiation of C2 cells compared with controls. All treatments suppressed ICF-II production but only TNF-alpha blocked IGFBP-5 secretion. TNF-alpha increased apoptotic cell death, which otherwise remained basal (low serum differentiation medium (LSM), FGF) or low (ceramide). Suppression of both IGFBP-5 and IGF-II secretion may explain why of all triggers tested, only TNF-alpha not only blocked differentiation, but also promoted cell death. This suggests a fundamental role of IGFBP-5 for maintaining muscle survival. Supporting this hypothesis, no increase in apoptosis was seen in IGFBP-5 cDNA transfected C2 cells after TNF-alpha treatment. In summary, the IGF system is essential for maintaining skeletal muscle cell survival and differentiation, and its suppression by TNF-alpha is fundamental regarding muscle wasting, and may be associated in vivo with cancer cachexia. J. Cell. Physiol. 183:330-337, 2000. (C) 2000 Wiley-Liss, Inc.

关键词：细胞凋亡/药物作用细胞凋亡/生理学细胞周期/药物作用细胞周期/生理学细胞系肌酸激酶/分析成纤维细胞生长因子2/药理学胰岛素样生长因子结合蛋白质5/生物合成胰岛素样生长因子结合蛋白质5/分泌胰岛素样生长因子Ⅱ/生物合成胰岛素样生长因子Ⅱ/分泌肌骨骼/细胞学肌骨骼/药物作用肌骨骼/生理学重组蛋白质类/生物合成重组蛋白质类/药理学第二信使系统鞘氨醇/类似物和衍生物鞘氨醇/药理学转染肿瘤坏死因子α/药理学动物人类小鼠

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Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy

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NATURE MEDICINE 2000年第10期6卷 1109-1114页

作者： Morita, Y Perez, GI Paris, F Miranda, SR Ehleiter, D Haimovitz-Friedman, A Fuks, Z Xie, ZH Reed, JC Schuchman, EH Kolesnick, RN Tilly, JL Harvard Univ Massachusetts Gen Hosp Sch Med Dept Obstet & GynecolVincent Ctr Reprod Biol Boston MA 02114 USA Mem Sloan Kettering Canc Ctr Dept Radiat Oncol New York NY 10021 USA Mem Sloan Kettering Canc Ctr Lab Signal Transduct New York NY 10021 USA Mt Sinai Sch Med Dept Human Genet New York NY 10029 USA Burnham Inst Program Apoptosis & Cell Death Res La Jolla CA 92037 USA

The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.

关键词：细胞凋亡/药物作用细胞凋亡/遗传学细胞凋亡/辐射效应细胞存活/遗传学剂量效应关系药物多柔比星/药理学溶血磷脂素类/药理学小鼠突变型卵母细胞/细胞学卵母细胞/药物作用卵母细胞/辐射效应鞘磷脂磷酸二酯酶/遗传学鞘磷脂磷酸二酯酶/代谢鞘磷脂类/代谢鞘氨醇/类似物和衍生物鞘氨醇/药理学动物女(雌)性男(雄)性小鼠

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p21-activated kinase 1 phosphorylates the death agonist Bad and protects cells from apoptosis

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MOLECULAR AND CELLULAR BIOLOGY 2000年第2期20卷 453-461页

作者： Schürmann, A Mooney, AF Sanders, LC Sells, MA Wang, HG Reed, JC Bokoch, GM Scripps Res Inst Dept Immunol La Jolla CA 92037 USA Rhein Westfal TH Aachen Fak Med Inst Pharmakol & Toxikol D-52057 Aachen Germany Scripps Res Inst Dept Cell Biol La Jolla CA 92037 USA Burnham Inst La Jolla CA 92037 USA Fox Chase Canc Ctr Philadelphia PA 19111 USA Univ S Florida H Lee Moffitt Canc Ctr & Res Inst Tampa FL 33612 USA

Bad is a critical regulatory component of the intrinsic cell death machinery that exerts its death-promoting effect upon heterodimerization with the antiapoptotic proteins Bcl-2 and Bcl-x(L). Growth factors promote cell survival through phosphorylation of Bad, resulting in its dissociation from Bcl-2 and Bcl-x(L) and its association with 14-3-3(tau). Survival of interleukin 3 (IL-3)-dependent FL5.12 lymphoid progenitor cells is attenuated upon treatment with the Rho GTPase-inactivating toxin B from Clostridium difficile. p21-activated kinase 1 (PAK1) is activated by IL-3 in FL5.12 cells, and this activation is reduced by the phosphatidylinositol 3-kinase inhibitor LY294002. Overexpression of a constitutively active PAK mutant (PAK1-T423E) promoted cell survival of FL5.12 and NIH 3T3 cells, while overexpression of the autoinhibitory domain of PAK (amino acids 83 to 149) enhanced apoptosis. PAK phosphorylates Bad in vitro and in vivo on Ser112 and Ser136, resulting in a markedly reduced interaction between Bad and Bcl-2 or Bcl-x(L) and the increased association of Bad with 14-3-3(tau). Our findings indicate that PAK inhibits the proapoptotic effects of Bad by direct phosphorylation and that PAK may play an important role in cell survival pathways.

关键词： 14-3-3蛋白质类细胞凋亡/药物作用载体蛋白质类/拮抗剂和抑制剂载体蛋白质类/遗传学载体蛋白质类/代谢细胞系细胞存活/药物作用酶激活/药物作用白细胞介素3/药理学突变/遗传学肽碎片/化学肽碎片/遗传学肽碎片/代谢磷酸肌醇3-激酶类/拮抗剂和抑制剂磷酸肌醇3-激酶类/代谢磷酰化磷酸丝氨酸/代谢蛋白质结合蛋白质丝氨酸苏氨酸激酶/化学蛋白质丝氨酸苏氨酸激酶/遗传学蛋白质丝氨酸苏氨酸激酶/代谢蛋白质类/代谢原癌基因蛋白质c-bcl-2/代谢信号传导/药物作用鞘氨醇/类似物和衍生物鞘氨醇/药理学酪氨酸单氧化酶 bcl相关死亡蛋白质 bcl-X蛋白质 cdc42GTP结合蛋白质/代谢 p21活化激酶类 ρGTP结合蛋白质类/拮抗剂和抑制剂 ρGTP结合蛋白质类/代谢动物小鼠

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Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate

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AMERICAN HEART JOURNAL 2003年第1期146卷 62-68页

作者： Deutschman, DH Carstens, JS Klepper, RL Smith, WS Page, MT Young, TR Gleason, LA Nakajima, N Sabbadini, RA San Diego State Univ Dept Biol San Diego CA 92182 USA San Diego State Univ SDSU Heart Inst San Diego CA 92182 USA Naval Med Ctr San Diego Div Cardiol San Diego CA USA Medlyte Inc San Diego CA USA

Background Sphingolipids are emerging as important signaling molecules that may be produced by cardiac tissue during ischemic stress or as a consequence of inflammation. Because both inflammation and myocardial ischemia are associated with coronary artery disease (CAD), a study was designed to test the ability of serum sphingolipids to predict obstructive CAD. Methods The study consisted of 308 consecutive patients undergoing coronary angiography for all indications. The primary data points were the assessment of coronary artery stenosis with angiography and the measurements of serum sphingolipids. Results In this diverse population, serum sphingosine-1-phosphate (S1P) was a significant predictor of CAD (P<.001). Multivariate analysis with logistic regression demonstrated that serum S1P was more predictive of obstructive CAD (odds ratio = 7.61) than the traditional risk factors (age, sex, family history of CAD, diabetes mellitus, lipid profile, hypertension, etc.). A 3-variable S1PC composite score was derived by combining the power of the S1P marker with the 2 most important risk factors, age and sex. The relationship between the S1PC and CAD scores was continuous and progressive, such that patients with elevated S1PC scores had higher occurrences of obstructive CAD. S1PC was also, predictive of disease,severity;53.2% of patients in the fourth S1PC quartile had 2 to 3 vessel CAD, whereas only 5.2% of patients in the first S1PC quartile had 2 to 3 vessel disease (RR = 10.2 for severity). Conclusions Serum S1P is a remarkably strong and robust predictor of both the occurrence and severity of coronary stenosis. An S1P-based composite score may be useful as a novel, non-invasive indicator of obstructive CAD.

关键词：方差分析生物学标记/血液 Logistic模型溶血磷脂素类危险因素疾病严重程度指数鞘氨醇/类似物和衍生物鞘氨醇/血液成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Structure-activity relationship of short-chain sphingoid bases as inhibitors of sphingosine kinase

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第21期9卷 3175-3180页

作者： De Jonghe, S Van Overmeire, I Poulton, S Hendrix, C Busson, R Van Calenbergh, S De Keukeleire, D Spiegel, S Herdewijn, P Univ Ghent Fac Pharmaceut Sci Med Chem Lab B-9000 Ghent Belgium Georgetown Univ Med Ctr Dept Biochem & Mol Biol Washington DC 20007 USA Katholieke Univ Leuven Rega Inst Med Chem Lab B-3000 Louvain Belgium

Short-chain sphinganine analogues 8, 9, 18, and 19 as well as 3-fluoro-sphingosine analogues 25 and 26 were synthesized. Their potential as sphingosine kinase inhibitors was investigated, in combination with previously synthesized sphingosine and fluorinated sphinganine analogues. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：细胞系酶抑制剂/化学合成酶抑制剂/药理学氟化合物/化学合成氟化合物/药理学溶血磷脂素类分子结构磷酸转移酶类(醇族体)/拮抗剂和抑制剂鞘氨醇/类似物和衍生物鞘氨醇/代谢鞘氨醇/药理学立体异构现象构效关系人类

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