果蝇碱性神经酰胺酶（DaCER）特征化及其在发育、存活和繁殖中的作用
|
摘要
神经酰胺酶能够水解神经酰胺生成鞘氨醇和脂肪酸。这些鞘脂质的代谢与多种生物(从酵母到哺乳动物)的细胞反应相关。通过本研究我们证明了果蝇BWA基因所编码的蛋白具有碱性神经酰胺酶的活性，并且这个蛋白在果蝇的鞘脂质代谢、发育、存活和繁殖中发挥重要的作用。以下是本研究获得的主要结果：
1．用人类神经酰胺酶作为关键词在果蝇基因组数据库中进行Blast搜索，我们发现了一个由果蝇洗脑基因(brain washing，BWA)编码的蛋白与人类神经酰胺酶1(ACER1)、人类神经酰胺酶2(ACER2)和人类神经酰胺酶3(ACER3)的蛋白序列分别具有35％、46％和26％的同源性。运用RT-PCR的方法我们克隆得到了BWA基因的全长cDNA。通过比对还发现，BWA编码的蛋白与其它的碱性神经酰胺酶也具有相同的氨基酸保守区域。用pSORTII软件可以预测到BWA的蛋白产物含有5个假定的跨膜区域，推测BWA编码的蛋白是多跨膜区域神经酰胺酶超家族中的一员。
2．在Tn细胞中过量表达BWA基因能够在pH 8.0、C24：1-ceramide作底物的条件下增加神经酰胺酶的活性，这说明BWA编码的蛋白具有神经酰胺酶的活性，因此我们将BWA重新命名为果蝇碱性神经酰胺酶(DaCER)。DaCER酶反应最适温度是35℃。我们还发现DaCER酶反应具有更广的pH范围，其中最佳pH值是8.0。
3．实时定量PCR的分析结果显示，DaCER的mRNA在果蝇卵巢中表达量最高，脑部和中肠其次，在其它部位只有少量的表达。DaCER在果蝇发育过程中蛹期的表达量上调。我们构建表达载体pEGFP-C1-DaCER，并将它转染HeLa细胞。荧光显微镜观察的结果显示，DaCER分布在细胞的质膜和高尔基复合体上。
4．DaCER的功能失活导致果蝇未成熟期的发育延迟但是寿命和生殖力却显著提高，说明DaCER在果蝇的发育、寿命和繁殖中起重要的作用。
5．由转座子插入造成的DaCER功能的失活导致果蝇体内鞘氨醇和二氢鞘氨醇的水平下降，特别是C_(16)鞘氨醇的水平显著减少。这与MAPP处理的体外实验的结果相一致。经过MAPP 72h处理的S2细胞内的C_(16)鞘氨醇的水平也显著的降低，表明DaCER功能的失活对鞘脂质的代谢有改变作用。
6．为了深入研究DaCER表达的下调在体外水平上对细胞的影响，用RNAi的方法将S2细胞中DaCER的表达量下调。实时定量PCR分析结果显示，转染了DaCER特异的双链RNA的S2细胞中，DaCER的mRNA水平显著降低，但是中性神经酰胺酶的表达有少量升高。流式细胞仪对DaCER下调后的S2细胞的细胞周期分析结果则显示DaCER表达量减少后，S期细胞所占的百分比与对照性比没有显著的差别。
总之，碱性神经酰胺酶DaCER在果蝇的鞘脂质代谢、发育、存活和繁殖中发挥重要的作用。
Ceramidases catalyze the hydrolysis of ceramides to generate sphingosine (SPH)and fatty acids. The metabolism of these sphingolipids is implicated in biologicalresponses in various organisms ranging from yeast to mammals. In this study, wedemonstrate that the protein product (DaCER) of the Drosophila BWA gene hasalkaline ceramidase activity and that it plays an important role in the metabolism ofsphingolipids, development, survival and reproduction in Drosophila melangaster.The primary results are as follows:
1. A Blast search of Drosophila melanogaster genomic database using humanalkaline ceramidases as queries revealed a putative protein encoded by the brainwashing gene (BWA) that exhibited a 35%, 46% and 26% identity in protein sequenceto the human alkaline ceramidases ACER1, ACER2 and ACER3, respectively. A full-lengthcDNA of BWA was cloned from Drosophila adults by reverse transcription - PCR(RT-PCR). It was also found that the BWA gene product contains multipleconserved domains shared among these alkaline ceramidases. Because the pSORTIIprogram predicted that the BWA consists of 5 putative transmembrane domains, thisgene may be a member of the multiple-transmembrane domain (MTD) ceramidasesuperfamily.
2. Overexpression of BWA in Tn cells increased ceramidase activity onC24:1-ceramide at pH 8.0, suggesting that BWA has alkaline ceramidase activity. Thuswe renamed it the Drosophila alkaline ceramidase, DaCER2. The optimal temperaturefor DaCER activity is 35℃. We also found that DaCER has a much broader pHoptimum, with highest activity at pH8.0.
3. qRT-PCR analysis showed that DaCER mRNA is expressed highest in theovary, moderately in the brain and midgut, and slightly in other organs, and thatDaCER expression is up-regulated at pupal stage during the development ofDrosophila. The plasmid pEGFP-Cl-DaCER was constructed and transfected intoHeLa cells. Fluorescence microscopy analysis showed that DaCER is localized tothe plasma membrane and Golgi complex.
4. DaCER inactivation leads to a delayed pre-adult development but anincreased lifespan and fecundity in Drosophila. These results suggest that DaCER hasan important role in the Drosophila development, longevity, and fecundity.
5. An inactivation of DaCER by insertional mutagenesis caused a decrease inthe levels of sphingosine and dihydrosphingosine, especially the C_(16) sphingosine. Thiswas consistent with in vitro assay for detemining the effect of MAPP on sphingosineslevels. The level of C_(16) sphingosine decreased significantly after 72h treatment ofMAPP. These results suggest that DaCER inactivation alters the metabolism ofsphingolipids.
6. To investigate whether DaCER down-regulation would have positive effectin vitro. Expression of DaCER in S2 cells was down-regulated by RNAi. qRT-PCRanalysis demonstrated that transfection of S2 cells with a dsRNA specifically againstDaCER caused a significant decrease in the level of DaCER mRNA and a littleincrease in the level of neutral ceramidase. However, FACS analysis revealed thatDaCER knockdown had no effect on the percentage of cells in the S-phase of the cellcycle.
In summary, Drosophila alkaline ceramidase (DaCER) plays an important role inthe fly sphingolipids metabolism, development, survival and reproduction.
1．用人类神经酰胺酶作为关键词在果蝇基因组数据库中进行Blast搜索，我们发现了一个由果蝇洗脑基因(brain washing，BWA)编码的蛋白与人类神经酰胺酶1(ACER1)、人类神经酰胺酶2(ACER2)和人类神经酰胺酶3(ACER3)的蛋白序列分别具有35％、46％和26％的同源性。运用RT-PCR的方法我们克隆得到了BWA基因的全长cDNA。通过比对还发现，BWA编码的蛋白与其它的碱性神经酰胺酶也具有相同的氨基酸保守区域。用pSORTII软件可以预测到BWA的蛋白产物含有5个假定的跨膜区域，推测BWA编码的蛋白是多跨膜区域神经酰胺酶超家族中的一员。
2．在Tn细胞中过量表达BWA基因能够在pH 8.0、C24：1-ceramide作底物的条件下增加神经酰胺酶的活性，这说明BWA编码的蛋白具有神经酰胺酶的活性，因此我们将BWA重新命名为果蝇碱性神经酰胺酶(DaCER)。DaCER酶反应最适温度是35℃。我们还发现DaCER酶反应具有更广的pH范围，其中最佳pH值是8.0。
3．实时定量PCR的分析结果显示，DaCER的mRNA在果蝇卵巢中表达量最高，脑部和中肠其次，在其它部位只有少量的表达。DaCER在果蝇发育过程中蛹期的表达量上调。我们构建表达载体pEGFP-C1-DaCER，并将它转染HeLa细胞。荧光显微镜观察的结果显示，DaCER分布在细胞的质膜和高尔基复合体上。
4．DaCER的功能失活导致果蝇未成熟期的发育延迟但是寿命和生殖力却显著提高，说明DaCER在果蝇的发育、寿命和繁殖中起重要的作用。
5．由转座子插入造成的DaCER功能的失活导致果蝇体内鞘氨醇和二氢鞘氨醇的水平下降，特别是C_(16)鞘氨醇的水平显著减少。这与MAPP处理的体外实验的结果相一致。经过MAPP 72h处理的S2细胞内的C_(16)鞘氨醇的水平也显著的降低，表明DaCER功能的失活对鞘脂质的代谢有改变作用。
6．为了深入研究DaCER表达的下调在体外水平上对细胞的影响，用RNAi的方法将S2细胞中DaCER的表达量下调。实时定量PCR分析结果显示，转染了DaCER特异的双链RNA的S2细胞中，DaCER的mRNA水平显著降低，但是中性神经酰胺酶的表达有少量升高。流式细胞仪对DaCER下调后的S2细胞的细胞周期分析结果则显示DaCER表达量减少后，S期细胞所占的百分比与对照性比没有显著的差别。
总之，碱性神经酰胺酶DaCER在果蝇的鞘脂质代谢、发育、存活和繁殖中发挥重要的作用。
Ceramidases catalyze the hydrolysis of ceramides to generate sphingosine (SPH)and fatty acids. The metabolism of these sphingolipids is implicated in biologicalresponses in various organisms ranging from yeast to mammals. In this study, wedemonstrate that the protein product (DaCER) of the Drosophila BWA gene hasalkaline ceramidase activity and that it plays an important role in the metabolism ofsphingolipids, development, survival and reproduction in Drosophila melangaster.The primary results are as follows:
1. A Blast search of Drosophila melanogaster genomic database using humanalkaline ceramidases as queries revealed a putative protein encoded by the brainwashing gene (BWA) that exhibited a 35%, 46% and 26% identity in protein sequenceto the human alkaline ceramidases ACER1, ACER2 and ACER3, respectively. A full-lengthcDNA of BWA was cloned from Drosophila adults by reverse transcription - PCR(RT-PCR). It was also found that the BWA gene product contains multipleconserved domains shared among these alkaline ceramidases. Because the pSORTIIprogram predicted that the BWA consists of 5 putative transmembrane domains, thisgene may be a member of the multiple-transmembrane domain (MTD) ceramidasesuperfamily.
2. Overexpression of BWA in Tn cells increased ceramidase activity onC24:1-ceramide at pH 8.0, suggesting that BWA has alkaline ceramidase activity. Thuswe renamed it the Drosophila alkaline ceramidase, DaCER2. The optimal temperaturefor DaCER activity is 35℃. We also found that DaCER has a much broader pHoptimum, with highest activity at pH8.0.
3. qRT-PCR analysis showed that DaCER mRNA is expressed highest in theovary, moderately in the brain and midgut, and slightly in other organs, and thatDaCER expression is up-regulated at pupal stage during the development ofDrosophila. The plasmid pEGFP-Cl-DaCER was constructed and transfected intoHeLa cells. Fluorescence microscopy analysis showed that DaCER is localized tothe plasma membrane and Golgi complex.
4. DaCER inactivation leads to a delayed pre-adult development but anincreased lifespan and fecundity in Drosophila. These results suggest that DaCER hasan important role in the Drosophila development, longevity, and fecundity.
5. An inactivation of DaCER by insertional mutagenesis caused a decrease inthe levels of sphingosine and dihydrosphingosine, especially the C_(16) sphingosine. Thiswas consistent with in vitro assay for detemining the effect of MAPP on sphingosineslevels. The level of C_(16) sphingosine decreased significantly after 72h treatment ofMAPP. These results suggest that DaCER inactivation alters the metabolism ofsphingolipids.
6. To investigate whether DaCER down-regulation would have positive effectin vitro. Expression of DaCER in S2 cells was down-regulated by RNAi. qRT-PCRanalysis demonstrated that transfection of S2 cells with a dsRNA specifically againstDaCER caused a significant decrease in the level of DaCER mRNA and a littleincrease in the level of neutral ceramidase. However, FACS analysis revealed thatDaCER knockdown had no effect on the percentage of cells in the S-phase of the cellcycle.
In summary, Drosophila alkaline ceramidase (DaCER) plays an important role inthe fly sphingolipids metabolism, development, survival and reproduction.
引文
Acharya, U. and J. K. Acharya (2005). "Enzymes of sphingolipid metabolism in Drosophila melanogaster." Cell Mol Life Sci 62(2): 128-42.
Acharya, U., M. B. Mowen, et al. (2004). "Ceramidase expression facilitates membrane turnover a and endocytosis of rhodopsin in photoreceptors." Proceedings of the National Academy of Sciences of the United States of America 101(7): 1922-1926.
Acharya, U., S. Patel, et al. (2003). "Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration." Science 299(5613): 1740-1743.
Adachi-Yamada, T., T. Gotoh, et al. (1999). "De novo synthesis of sphingolipids is required for cell survival by down-regulating c-Jun N-terminal kinase in Drosophila imaginal discs." Molecular and Cellular Biology 19(10): 7276-7286.
Adams, M. D., S. E. Celniker, et al. (2000). "The genome sequence of Drosophila melanogaster." Science 287(5461): 2185-2195.
Aerts, A. M., P. Zabrocki, et al. (2008). "Ydclp ceramidase triggers organelle fragmentation, apoptosis and accelerated ageing in yeast." Cellular and Molecular Life Sciences 65(12): 1933-1942.
Ahn, J. H., Y. G. Ko, et al. (1999). "Suppression of ceramide-mediated apoptosis by HSP70." Molecules and Cells 9(2): 200-206.
Akiyama, S. K., S. S. Yamada, et al. (1989). "Analysis of the Role of Glycosylation of the Human Fibronectin Receptor." Journal of Biological Chemistry 264(30):18011-18018.
Alessenko, A. V., V. G. Korobko, et al. (1997). "Relation of biological activity of mutant forms of recombinant human tumor necrosis factor alpha and accumulation of sphingosine in murine liver." Biochemistry and Molecular Biology International 42(1): 143-154.
Ashburner, M., C. Detwiler, et al. (1983). "The Genetics of a Small Autosomal Region of Drosophila-Melanogaster Containing the Structural Gene for Alcohol-Dehydrogenase .6. Induced Revertants of Scutoid." Genetics 104(3): 405-431.
Auge, N., M. Nikolova-Karakashian, et al. (1999). "Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase." Journal of Biological Chemistry 274(31): 21533-21538.
Beeler, T., D. Bacikova, et al. (1998). "The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2 Delta mutant." Journal of Biological Chemistry 273(46): 30688-30694.
Bernardo, K., R. Hurwitz, et al. (1995). "Purification, Characterization, and Biosynthesis of Human Acid Ceramidase." Journal of Biological Chemistry 270(19): 11098-11102.
Bieber, L. L., J. D. Oconnor, et al. (1969). "Occurrence of Tetradecasphing-4-Enine and Hexadecasphing-4-Enine as Principal Sphingosines of Musca Domestica Larvae and Adults." Biochimica Et Biophysica Acta 187(1): 157-&.
Blazquez, C, I. Galve-Roperh, et al. (2000). "De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase." Faseb Journal 14(14): 2315-2322.
Boquet, I., R. Hitier, et al. (2000). "Central brain postembryonic development in Drosophila: Implication of genes expressed at the interhemispheric junction." Journal of Neurobiology 42(1): 33-48.
Bourbon, N. A., J. Yun, et al. (2000). "Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex." Journal of Biological Chemistry 275(45): 35617-35623.
Bozcuk, A. N. (1972). "DNA-Synthesis in Absence of Somatic Cell-Division Associated with Aging in Drosophila-Subobscura." Experimental Gerontology 7(3): 147-&.
Brinkmann, U. (1998). "CAS, the human homologue of the yeast chromosome-segregation gene CSE1, in proliferation, apoptosis, and cancer." American Journal of Human Genetics 62(3): 509-513.
Buede, R., C. Rinkerschaffer, et al. (1991). "Cloning and Characterization of Lcbl, a Saccharomyces Gene Required for Biosynthesis of the Long-Chain Base Component of Sphingolipids." Journal of Bacteriology 173(14): 4325-4332.
Burek, C, J. Roth, et al. (2001). "The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells." Oncogene 20(45): 6493-6502.
Chalfant, C. E., K. Rathman, et al. (2002). "De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells - Dependence on protein phosphatase-1." Journal of Biological Chemistry 277(15): 12587-12595.
Chang, H. C, L. H. Tsai, et al. (2001). "Role of AKT kinase in sphingosine-induced apoptosis in human hepatoma cells." Journal of Cellular Physiology 188(2):188-193.
Coussin, R, R. H. Scott, et al. (2002). "Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles differential role in vasoconstriction." Circulation Research 91(2): 151-157.
Cuvillier, O., L. Edsall, et al. (2000). "Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells." Journal of Biological Chemistry 275(21): 15691-15700.
Cuvillier, O., V. E. Nava, et al. (2001). "Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells." Cell Death and Differentiation 8(2): 162-171.
Cuvillier, O., D. S. Rosenthal, et al. (1998). "Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes." Journal of Biological Chemistry 273(5): 2910-2916.
Dbaibo, G. S., M. Y. Pushkareva, et al. (1995). "Retinoblastoma Gene-Product as a Downstream Target for a Ceramide-Dependent Pathway of Growth Arrest." Proceedings of the National Academy of Sciences of the United States of America 92(5): 1347-1351.
Dennis, R. D., R. Geyer, et al. (1985). "Glycosphingolipids in Insects - Chemical Structures of Ceramide Monosaccharide, Disaccharide, and Trisaccharide from Pupae of Calliphora-Vicina (Insecta, Diptera)." European Journal of Biochemistry 146(1): 51-58.
Dennis, R. D., R. Geyer, et al. (1985). "Glycosphingolipids in Insects - Chemical Structures of Ceramide Tetrasaccharide, Pentasaccharide, Hexasaccharide, and Heptasaccharide from Calliphora-Vicina Pupae (Insecta, Diptera)." Journal of Biological Chemistry 260(9): 5370-5375.
Dickson, R. C. (2008). "New insights into sphingolipid metabolism and function in budding yeast." Journal of Lipid Research 49(5): 909-921.
Dickson, R. C. and R. L. Lester (1999). "Metabolism and selected functions of sphingolipids in the yeast Saccharomyces cerevisiae." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1438(3): 305-321.
Dickson, R. C, R. L. Lester, et al. (2000). "Serine palmitoyltransferase." Sphingolipid Metabolism and Cell Signaling, Pt A 311: 3-9.
Dickson, R. C, C. Sumanasekera, et al. (2006). "Functions and metabolism of sphingolipids in Saccharomyces cerevisiae." Progress in Lipid Research 45(6):447-465.
Dmello, N. P., A. M. Childress, et al. (1994). "Cloning and Characterization of Lagl, a Longevity-Assurance Gene in Yeast." Journal of Biological Chemistry 269(22):15451-15459.
Dolph, P. J., R. Ranganathan, et al. (1993). "Arrestin Function in Inactivation ofG-Protein Coupled Receptor Rhodopsin Invivo." Science 260(5116): 1910-1916.
Duan, R. D. (2006). "Alkaline sphingomyelinase: An old enzyme with novel implications." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1761(3): 281-291.
El Bawab, S., A. Bielawska, et al. (1999). "Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain." Journal of Biological Chemistry 274(39): 27948-27955.
El Bawab, S., P. Roddy, et al. (2000). "Molecular cloning and characterization of a human mitochondrial ceramidase." Journal of Biological Chemistry 275(28):21508-21513.
Eliyahu, E., J. H. Park, et al. (2007). "Acid ceramidase is a novel factor required for early embryo survival." Faseb Journal 21(7): 1403-1409.
Elojeimy, S., X. Liu, et al. (2007). "Role of acid ceramidase in resistance to FasL: Therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy." Molecular Therapy 15(7): 1259-1263.
Elsen, L., R. Betz, et al. (2002). "Identification of ceramide binding proteins in neuronal cells: A critical point of view." Neurochemical Research 27(7-8):717-727.
English, D., J. G. N. Garcia, et al. (2001). "Platelet-released phospholipids link haemostasis and angiogenesis." Cardiovascular Research 49(3): 588-599.
Franzen, R., A. Pautz, et al. (2001). "Interleukin-1 beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells." Journal of Biological Chemistry 276(38): 35382-35389.
Fujita, Y., E. Ohama, et al. (2006). "Fragmentation of Golgi apparatus of nigral neurons with alpha-synuclein-positive inclusions in patients with Parkinson's disease." Acta Neuropathologica 112(3): 261-265.
Funato, K., R. Lombardi, et al. (2003). "Lcb4p is a key regulator of ceramide synthesis from exogenous long chain sphingoid base in Saccharomyces cerevisiae." Journal of Biological Chemistry 278(9): 7325-7334.
Futerman, A. H. and Y. A. Hannun (2004), "The complex life of simple sphingolipids." Embo Reports 5(8): 777-782.
Futerman, A. H. and H. Riezman (2005). "The ins and outs of sphingolipid synthesis." Trends in Cell Biology 15(6): 312-318.
Fyrst, H., D. R. Herr, et al. (2004). "Characterization of free endogenous C-14 and C-16 sphingoid bases from Drosophila melanogaster." Journal of Lipid Research 45(1): 54-62.
Galve-Roperh, I., D. Rueda, et al. (2002). "Mechanism of extracellular signal-regulated kinase activation by the CB1 cannabinoid receptor." Molecular Pharmacology 62(6): 1385-1392.
Gatt, S. (1963). "Enzymic Hydrolysis and Synthesis of Ceramides." Journal of Biological Chemistry 238(9): 3131-&.
Goetzl, E. J., W. G. Wang, et al. (2007). "Sphingosine 1-phosphate as an intracellular messenger and extracellular mediator in immunity." Acta Paediatrica 96: 49-52.
Goni, F. M. and A. Alonso (2002). "Sphingomyelinases: enzymology and membrane activity." Febs Letters 531(1): 38-46.
Hanada, K. (2003). "Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1632(1-2): 16-30.
Hanada, K., T. Hara, et al. (1998). "Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin - Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase." Journal of Biological Chemistry 273(50): 33787-33794.
Hanada, K., K. Kumagai, et al. (2003). "Molecular machinery for non-vesicular trafficking of ceramide." Nature 426(6968): 803-809.
Hannun, Y. A. and R. M. Bell (1989). "Regulation of Protein Kinase-C by Sphingosine and Lysosphingolipids." Clinica Chimica Acta 185(3): 333-346.
Hannun, Y. A. and C. Luberto (2004). "Lipid metabolism: Ceramide transfer protein adds a new dimension." Current Biology 14(4): R163-R165.
Hannun, Y. A. and L. M. Obeid (1997). "Mechanisms of ceramide-mediated apoptosis." Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury 3 407: 145-149.
Hara, S., S. Nakashima, et al. (2004). "p53-independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis." Cell Death and Differentiation 11(8): 853-861.
He, X. X., N. Okino, et al. (2003). "Purification and characterization of recombinant, human acid ceramidase - Catalytic reactions and interactions with acid sphingomyelinase." Journal of Biological Chemistry 278(35): 32978-32986.
Helfand, S. L. and B. Rogina (2003). "Molecular genetics of aging in the fly: is this the end of the beginning?" Bioessays 25(2): 134-141.
Herr, D. R., H. Fyrst, et al. (2004). "Characterization of the Drosophila sphingosinekinases and requirement for Sk2 in normal reproductive function." Journal of Biological Chemistry 279(13): 12685-12694.
Herr, D. R., H. Fyrst, et al. (2003). "Sply regulation of sphingolipid signaling molecules is essential for Drosophila development." Development 130(11):2443-2453.
Hildenbr.Gr, T. Abraham, et al. (1971). "Metabolism of Ceramide Phosphorylethanolamine, Phosphatidylinositol, Phosphatidylserine and Phosphatidylglycerol by Housefly Larvae." Lipids 6(7): 508-&.
Hla, T. (2003). "Signaling and biological actions of sphingosine 1-phosphate." Pharmacological Research 47(5): 401-407.
Hoekstra, D., O. Maier, et al. (2003). "Membrane dynamics and cell polarity: the role of sphingolipids." Journal of Lipid Research 44(5): 869-877.
Holthuis, J. C. M., T. Pomorski, et al. (2001). "The organizing potential of sphingolipids in intracellular membrane transport." Physiological Reviews 81(4):1689-1723.
Holzenberger, M., J. Dupont, et al. (2003). "IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice." Nature 421(6919): 182-187.
Houben, E., W. M. Holleran, et al. (2006). "Differentiation-associated expression of ceramidase isoforms in cultured keratinocytes and epidermis." Journal of Lipid Research 47(5): 1063-1070.
Hu, W., R. J. Xu, et al. (2005). "Golgi fragmentation is associated with ceramide-induced cellular effects." Molecular Biology of the Cell 16(3):1555-1567.
Huwiler, A., J. Brunner, et al. (1996). "Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase." Proceedings of the National Academy of Sciences of the United States of America 93(14):6959-6963.
Huwiler, A., T. Kolter, et al. (2000). "Physiology and pathophysiology of sphingolipid metabolism and signaling." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1485(2-3): 63-99.
Igarashi, Y., S. Hakomori, et al. (1989). "Effect of Chemically Well-Defined Sphingosine and Its N-Methyl Derivatives on Protein Kinase-C and Src Kinase-Activities." Biochemistry 28(17): 6796-6800.
Ikeda, H., Y. Yatomi, et al. (2000). "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells (vol 279, pg G304, 2000)." American Journal of Physiology-Gastrointestinal and Liver Physiology 279(5):U1-U1.
Ito, K. and Y. Hotta (1992). "Proliferation Pattern of Postembryonic Neuroblasts in the Brain of Drosophila-Melanogaster." Developmental Biology 149(1): 134-148.
Jarvis, W. D., F. A. Fornari, et al. (1997). "Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine." Molecular Pharmacology 52(6): 935-947.
Jefferson, A. B. and H. Schulman (1988). "Sphingosine Inhibits Calmodulin-Dependent Enzymes." Journal of Biological Chemistry 263(30):15241-15244.
Kagedal, K., M. Zhao, et al. (2001). "Sphingosine-induced apoptosis is dependent on lysosomal proteases." Biochemical Journal 359: 335-343.
Kango-Singh, M. and G. Haider (2004). "Drosophila as an emerging model to study metastasis." Genome Biology 5(4): -.
Karim, F. D., H. C. Chang, et al. (1996). "A screen for genes that function downstream of Rasl during Drosophila eye development." Genetics 143(1):315-329.
Katsuma, S., Y. Hada, et al. (2002). "Signalling mechanisms in sphingosine 1-phosphate-promoted mesangial cell proliferation." Genes to Cells 7(12):1217-1230.
Kellokumpu, S., R. Sormunen, et al. (2002). "Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH." Febs Letters 516(1-3): 217-224.
Kernan, M, D. Cowan, et al. (1994). "Genetic Dissection of Mechanosensory Transduction - Mechanoreception-Defective Mutations of Drosophila." Neuron 12(6): 1195-1206.
Kim, D. S., S. Y. Kim, et al. (2004). "Sphingosine-1-phosphate inhibits human keratinocyte proliferation via Akt/protein kinase B inactivation." Cellular Signalling 16(1): 89-95.
Kim, L. T., S. Ishihara, et al. (1992). "Altered Glycosylation and Cell-Surface Expression of Beta-1 Integrin Receptors during Keratinocyte Activation." Journal of Cell Science 103: 743-753.
Kim, S., 1. Hong, et al. (2006). "Phytosphingosine stimulates the differentiation of human keratinocytes and inhibits TPA-induced inflammatory epidermal hyperplasia in hairless mouse skin." Molecular Medicine 12(1-3): 17-24.
Kluk, M. J. and T. Hla (2001). "Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration." Circulation Research 89(6): 496-502.
Kohno, M., M. Momoi, et al. (2006). "Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation." Molecular and Cellular Biology 26(19): 7211-7223.
Kolter, T., R. L. Proia, et al. (2002). "Combinatorial ganglioside biosynthesis." Journal of Biological Chemistry 277(29): 25859-25862.
Kono, M., J. L. Dreier, et al. (2006). "Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids." Journal of Biological Chemistry 281(11): 7324-7331.
Kowald, A. and T. B. L. Kirkwood (1994). "Towards a Network Theory of Aging - a Model Combining the Free-Radical Theory and the Protein Error Theory." Journal of Theoretical Biology 168(1): 75-94.
Krown, K. A., M. T. Page, et al. (1996). "Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes - Involvement of the sphingolipid signaling cascade in cardiac cell death." Journal of Clinical Investigation 98(12):2854-2865.
Lee, J. Y., Y A. Hannun, et al. (1996). "Ceramide inactivates cellular protein kinase C alpha." Journal of Biological Chemistry 271(22): 13169-13174.
Lee, M. J., S. Thangada, et al. (1999). "Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate." Cell 99(3):301-312.
Lepine, S., B. Lakatos, et al. (2004). "Sphingosine contributes to glucocorticoid-induced apoptosis of thymocytes independently of the mitochondrial pathway." Journal of Immunology 173(6): 3783-3790.
Lepine, S., B. Lakatos, et al. (2002). "Involvement of sphingosine in dexamethasone-induced thymocyte apoptosis." Cell Signaling, Transcription, and Translation as Therapeutic Targets 973: 190-193.
Li, C. M., J. H. Park, et al. (2002). "Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes (vol 79, pg 218, 2002)." Genomics 79(6): 890-890.
Li, G. C, H. Alexander, et al. (2000). "Molecular basis for resistance to the anticancer drug cisplatin in Dictyostelium." Microbiology-Uk 146: 2219-2227.
Li, G. C, C. Foote, et al. (2001). "Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum." Development 128(18):3473-3483.
Libera, L. D., R. Sabbadini, et al. (2001). "Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine." Journal of Molecular and Cellular Cardiology 33(10): 1871-1878.
Liu, Y. J., R. Wada, et al. (2000). "Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation." Journal of Clinical Investigation 106(8): 951-961.
Lu, F. G. and C. S. Wong (2004). "Radiation-induced apoptosis of oligodendrocytes and its association with increased ceramide and down-regulated protein kinase B/Akt activity." International Journal of Radiation Biology 80(1): 39-51.
Mao, C. G. and L. M. Obeid (2008). "Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1781(9): 424-434.
Mao, C. G, R. J. Xu, et al. (2000). "Cloning of an alkaline ceramidase from Saccharomyces cerevisiae - An enzyme with reverse (CoA-independent) ceramide synthase activity." Journal of Biological Chemistry 275(10):6876-6884.
Mao, C. G., R. J. Xu, et al. (2000). "Cloning and characterization of a Saccharomyces cerevisiae alkaline ceramidase with specificity for dihydroceramide." Journal of Biological Chemistry 275(40): 31369-31378.
Mao, C. G, R. J. Xu, et al. (2001). "Cloning and characterization of a novel human alkaline ceramidase - A mammalian enzyme that hydrolyzes phytoceramide." Journal of Biological Chemistry 276(28): 26577-26588.
Mao, C. G, R. J. Xu, et al. (2003). "Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase - An enzyme that preferentially regulates metabolism of very long chain ceramides." Journal of Biological Chemistry 278(33): 31184-31191.
Mattie, M., G. Brooker, et al. (1994). "Sphingosine-1-Phosphate, a Putative 2nd Messenger, Mobilizes Calcium from Internal Stores Via an Inositol Trisphosphate-Independent Pathway." Journal of Biological Chemistry 269(5):3181-3188.
Megidish, T., J. Cooper, et al. (1998). "A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein." Journal of Biological Chemistry 273(34): 21834-21845.
Menaldino, D. S., A. Bushnev, et al. (2003). "Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action." Pharmacological Research 47(5): 373-381.
Merrill, A. H. (2002). "De novo sphingolipid biosynthesis: A necessary, but dangerous, pathway." Journal of Biological Chemistry 277(29): 25843-25846.
Merrill, A. H., E. M. Schmelz, et al. (1997). "Sphingolipids - The enigmatic lipid class: Biochemistry, physiology, and pathophysiology." Toxicology and Applied Pharmacology 142(1): 208-225.
Michaud, N. R., M. Therrien, et al. (1997). "KSR stimulates Raf-1 activity in a kinase-independent manner." Proceedings of the National Academy of Sciences of the United States of America 94(24): 12792-12796.
Mizugishi, K., C. L. Li, et al. (2007). "Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice." Journal of Clinical Investigation 117(10): 2993-3006.
Mizugishi, K., T. Yamashita, et al. (2005). "Essential role for sphingosine kinases in neural and vascular development." Molecular and Cellular Biology 25(24):11113-11121.
Mizutani, Y., A. Kihara, et al. (2004). "Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation." Febs Letters 563(1-3): 93-97.
Momoi, T., Y. Benyoseph, et al. (1982). "Substrate-Specificities of Acid and Alkaline Ceramidases in Fibroblasts from Patients with Farber Disease and Controls." Biochemical Journal 205(2): 419-425.
Monick, M. M., R. K. Mallampalli, et al. (2004). "Cooperative prosurvival activity by ERK and Akt in human alveolar macrophages is dependent on high levels of acid ceramidase activity." Journal of Immunology 173(1): 123-135.
Morales, A., R. Paris, et al. (2007). "Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo." Oncogene 26(6): 905-916.
Muller, G, P. Storz, et al. (1998). "Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling." Embo Journal 17(3): 732-742.
Nagahara, Y., T. Shinomiya, et al. (2005). "Phytosphingosine induced mitochondria-involved apoptosis." Cancer Science 96(2): 83-92.
Nussleinvolhard, C. and E. Wieschaus (1980). "Mutations Affecting Segment Number and Polarity in Drosophila." Nature 287(5785): 795-801.
Obeid, L. A., Y. Okamoto, et al. (2002). "Yeast sphingolipids: metabolism and biology." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1585(2-3): 163-171.
Ohlsson, L., C. Palmberg, et al. (2007). "Purification and characterization of human intestinal neutral ceramidase." Naunyn-Schmiedebergs Archives of Pharmacology 374(4): 329-330.
Ohta, H., E. A. Sweeney, et al. (1995). "Induction of Apoptosis by Sphingosine in Human Leukemic H1-60 Cells - a Possible Endogenous Modulator of Apoptotic DNA Fragmentation Occurring during Phorbol Ester-Induced Differentiation." Cancer Research 55(3): 691-697.
Okino, N., S. Ichinose, et al. (1999). "Molecular cloning, sequencing, and expression of the gene encoding alkaline ceramidase from Pseudomonas aeruginosa. Cloning of a ceramidase homologue from Mycobacterium tuberculosis." J Biol Chem 274(51): 36616-22.
Okino, N., M. Tani, et al. (1998). "Purification and characterization of a novel ceramidase from Pseudomonas aeruginosa." Journal of Biological Chemistry 273(23): 14368-14373.
Olivera, A., T. Kohama, et al. (1999). "Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival." Journal of Cell Biology 147(3): 545-557.
Olsson, M., R. D. Duan, et al. (2004). "Rat intestinal ceramidase: purification, properties, and physiological relevance." American Journal of Physiology-Gastrointestinal and Liver Physiology 287(4): G929-G937.
Osawa, Y., H. Uchinami, et al. (2005). "Roles for C-16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha." Journal of Biological Chemistry 280(30): 27879-27887.
Paik, J. H., S. S. Chae, et al. (2001). "Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha(v)beta(3)- and beta(1)-containing integrins." Journal of Biological Chemistry 276(15): 11830-11837.
Pelagalli, A., M. A. Belisario, et al. (1999). "The mycotoxin fumonisin Bl inhibits integrin-mediated cell-matrix adhesion." Biochimie 81(10): 1003-1008.
Pelled, D., T. Raveh, et al. (2002). "Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons." Journal of Biological Chemistry 277(3): 1957-1961.
Phan, V. H., D. R. Herr, et al. (2007). "Disruption of sphingolipid metabolism elicits apoptosis-associated reproductive defects in Drosophila." Developmental Biology 309(2): 329-341.
Powers, R. W., M. Kaeberlein, et al. (2006). "Extension of chronological life span in yeast by decreased TOR pathway signaling." Genes & Development 20(2):174-184.
Rao, R. P., C. Yuan, et al. (2007). "Ceramide transfer protein function is essential for normal oxidative stress response and lifespan." Proceedings of the National Academy of Sciences of the United States of America 104(27): 11364-11369.
Renault, A. D., M. Starz-Gaiano, et al. (2002). "Metabolism of sphingosine 1-phosphate and lysophosphatidic acid: a genome wide analysis of gene expression in Drosophila." Mechanisms of Development 119: S293-S301.
Riebeling, C, J. C. Allegood, et al. (2003). "Two mammalian longevity assurance gene (LAG1) family members, trh 1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors." Journal of Biological Chemistry 278(44): 43452-43459.
Rietveld, A., S. Neutz, et al. (1999). "Association of sterol- and glycosylphosphatidylinositol-linked proteins with Drosophila raft lipid microdomains." Journal of Biological Chemistry 274(17): 12049-12054.
Riezman, H. and G. van Meer (2004). "Lipid pickup and delivery." Nature Cell Biology 6(1): 15-16.
Roccamo, A. M, M. F. Pediconi, et al. (1999). "Cells defective in sphingolipids biosynthesis express low amounts of muscle nicotinic acetylcholine receptor." European Journal of Neuroscience 11(5): 1615-1623.
Rong, Y. S. (2002). "Gene targeting by homologous recombination: a powerful addition to the genetic arsenal for Drosophila geneticists." Biochemical and Biophysical Research Communications 297(1): 1-5.
Rubin, G. M, M. D. Yandell, et al. (2000). "Comparative genomics of the eukaryotes." Science 287(5461): 2204-2215.
Ruvolo, P. P. (2003). "Intracellular signal transduction pathways activated by ceramide and its metabolites." Pharmacological Research 47(5): 383-392.
Ruvolo, P. P., X. M. Deng, et al. (1999). "Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A." Journal of Biological Chemistry 274(29): 20296-20300.
Ruvolo, P. P., F. Q. Gao, et al. (2001). "Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX." Journal of Biological Chemistry 276(15): 11754-11758.
Saad, A. F., W. D. Meacham, et al. (2007). "The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy." Cancer Biology & Therapy 6(9): 1455-1460.
Saba, J. D. and T. Hla (2004). "Point-counterpoint of sphingosine 1-phosphate metabolism." Circulation Research 94(6): 724-734.
Sakagami, H. and H. Kondo (1997). "Molecular cloning and developmental expression of a rat homoiogue of death-associated protein kinase in the nervous system." Molecular Brain Research 52(2): 249-256.
Samet, D. and Y. Barenholz (1999). "Characterization of acidic and neutral sphingomyelinase activities in crude extracts of HL-60 cells." Chemistry and Physics of Lipids 102(1-2): 65-77.
Schmelz, E. M., P. C. Roberts, et al. (2001). "Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids." Cancer Research 61(18): 6723-6729.
Schutze, S., M. Wickel, et al. (2000). "Use of affinity chromatography and TID-ceramide photoaffinity labeling for detection of ceramide-binding proteins." Sphingolipid Metabolism and Cell Signaling, Pt B 312: 429-438.
Schwientek, T., B. Keck, et al. (2002). "The Drosophila gene brainiac encodes a glycosyltransferase putatively involved in glycosphingolipid synthesis." Journal of Biological Chemistry 277(36): 32421-32429.
Segui, B., C. Bezombes, et al. (2000). "Stress-induced apoptosis is not mediated by endolysosomal ceramide." Faseb Journal 14(1): 36-47.
Sekizawa, Y, T. Kubo, et al. (1997). "Molecular cloning of cDNA for lysenin, a novel protein in the earthworm Eisenia foetida that causes contraction of rat vascular smooth muscle." Gene 191(1): 97-102.
Seppo, A., M. Moreland, et al. (2000). "Zwitterionic and acidic glycosphingolipids of the Drosophila melanogaster embryo." European Journal of Biochemistry 267(12): 3549-3558.
Seppo, A. and M. Tiemeyer (2000). "Function and structure of Drosophila glycans." Glycobiology 10(8): 751-760.
Shayman, J. A. (2000). "Sphingolipids." Kidney International 58(1): 11-26. Shin, J., H. Lee, et al. (2007). "Sphingosine 1-phosphate triggers apoptotic signal for B16 melanoma cells via prolonged ERK and caspase-8 activation." Journal of Investigative Dermatology 127: S96-S96.
Shirakabe, K., K. Yamaguchi, et al. (1997). "TAK1 mediates the ceramide signaling to stress-activated protein kinase c-Jun N-terminal kinase." Journal of Biological Chemistry 272(13): 8141-8144.
Solomon, J. C, K. Sharma, et al. (2003). "A novel role for sphingolipid intermediates in activation-induced cell death in T cells." Cell Death and Differentiation 10(2):193-202.
Spradling, A. C, D. Stern, et al. (1999). "The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital drosophila genes." Genetics 153(1): 135-177.
Stapleton, M., G. C. Liao, et al. (2002). "The Drosophila gene collection: Identification of putative full-length cDNAs for 70% of D-melanogaster genes." Genome Research 12(8): 1294-1300.
Stieber, A., J. O. Gonatas, et al. (2004). "Disruption of the structure of the Golgi apparatus and the function of the secretory pathway by mutants G93A and G85R of Cu, Zn superoxide dismutase (SOD1) of familial amyotrophic lateral sclerosis." Journal of the Neurological Sciences 219(1-2): 45-53.
Stieber, A., Z. Mourelatos, et al. (1996). "In Alzheimer's disease the golgi apparatus of a population of neurons without neurofibrillary tangles is fragmented and atrophic." American Journal of Pathology 148(2): 415-426.
Stoica, B. A., V. A. Movsesyan, et al. (2003). "Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3 beta, and induction of the mitochondrial-dependent intrinsic caspase pathway." Molecular and Cellular Neuroscience 22(3): 365-382.
Strelow, A., K. Bernardo, et al. (2000). "Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death." Journal of Experimental Medicine 192(5): 601-611.
Sugita, M., M. Williams, et al. (1975). "Ceramidase and Ceramide Synthesis in Human Kidney and Cerebellum - Description of a New Alkaline Ceramidase." Biochimica Et Biophysica Acta 398(1): 125-131.
Sugiura, M., K. Kono, et al. (2002). "Ceramide kinase, a novel lipid kinase - Molecular cloning and functional characterization." Journal of Biological Chemistry 277(26): 23294-23300.
Sun, W., R. J. Xu, et al. (2008). "Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes." Journal of Investigative Dermatology 128(2): 389-397.
Suzuki, E., K. Handa, et al. (2004). "Sphingosine-dependent apoptosis: A unified concept based on multiple mechanisms operating in concert." Proceedings of the National Academy of Sciences of the United States of America 101(41):14788-14793.
Sweeney, E. A., C. Sakakura, et al. (1996). "Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines." International Journal of Cancer 66(3): 358-366.
Tani, M., Y. Igarashi, et al. (2005). "Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu." Journal of Biological Chemistry 280(44): 36592-36600.
Tani, M., N. Okino, et al. (2000). "Purification and characterization of a neutral ceramidase from mouse liver - A single protein catalyzes the reversible reaction in which ceramide is both hydrolyzed and synthesized." Journal of Biological Chemistry 275(5): 3462-3468.
Tani, M, N. Okino, et al. (2000). "Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase - A novel but highly conserved gene family of neutral/alkaline ceramidases." Journal of Biological Chemistry 275(15):11229-11234.
Tanimoto, T., Z. G. Jin, et al. (2002). "Transactivation of vascular endothelial growth factor (VEGF) receptor FIK-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS)." Journal of Biological Chemistry 277(45): 42997-43001.
Tapon, N. (2003). "Modeling transformation and metastasis in Drosophila." Cancer Cell 4(5): 333-335.
Tatar, M., A. Bartke, et al. (2003). "The endocrine regulation of aging by insulin-like signals." Science 299(5611): 1346-1351.
Tenenbaum, D. (2003). "What's all the buzz? Fruit flies provide unique model for cancer research." Journal of the National Cancer Institute 95(23): 1742-1744.
Thon, L., H. Mohlig, et al. (2005). "Ceramide mediates caspase-independent programmed cell death." Faseb Journal 19(14): 1945-1956.
Van Brocklyn, J. R., C. A. Letterle, et al. (2002). "Sphingosine-1-phosphate stimulates human glioma cell proliferation through G(i)-coupled receptors: role of ERK MAP kinase and phosphatidylinositol 3-kinase beta." Cancer Letters 181(2):195-204.
Wandall, H. H., J. W. Pedersen, et al. (2003). "Drosophila egghead encodes beta 1,4-mannosyltransferase predicted to form the immediate precursor glycosphingolipid substrate for brainiac." Journal of Biological Chemistry 278(3):1411-1414.
Wayne, M. L. and L. M. Mclntyre (2002). "Combining mapping and arraying: An approach to candidate gene identification." Proceedings of the National Academy of Sciences of the United States of America 99(23): 14903-14906.
Wells, G. B. and R. L. Lester (1983). "The Isolation and Characterization of a Mutant Strain of Saccharomyces-Cerevisiae That Requires a Long-Chain Base for Growth and for Synthesis of Phosphosphingolipids." Journal of Biological Chemistry 258(17): 200-203.
Williams, R. D., E. Wang, et al. (1984). "Enzymology of Long-Chain Base Synthesis by Liver - Characterization of Serine Palmitoyltransferase in Rat-Liver Microsomes." Archives of Biochemistry and Biophysics 228(1): 282-291.
Xu, R. J., J. F. Jin, et al. (2006). "Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and SIP." Faseb Journal 20(11):1813-1825.
Yamaoka, S., M. Miyaji, et al. (2004). "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells." Journal of Biological Chemistry 279(18):18688-18693.
Yang, S. N. (2000). "Ceramide-induced sustained depression of synaptic currents mediated by ionotropic glutamate receptors in the hippocampus: An essential role of postsynaptic protein phosphatases." Neuroscience 96(2): 253-258.
Yoshimura, Y., N. Okino, et al. (2002). "Molecular cloning and characterization of a secretory neutral ceramidase of Drosophila melanogaster." Journal ofBiochemistry 132(2): 229-236.
Yoshimura, Y, M. Tani, et al. (2004). "Molecular cloning and functional analysis of zebrafish neutral ceramidase." Journal of Biological Chemistry 279(42):44012-44022.
Zhang, H., N. N. Desai, et al. (1991). "Sphingosine-1-Phosphate, a Novel Lipid, Involved in Cellular Proliferation." Journal of Cell Biology 114(1): 155-167.
Zhang, Y. H., B. Yao, et al. (1997). "Kinase suppressor of Ras is ceramide-activated protein kinase." Cell 89(1): 63-72.
Zhou, H. L., S. K. Summers, et al. (1998). "Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis." Journal of Biological Chemistry 273(26): 16568-16575.
Acharya, U., M. B. Mowen, et al. (2004). "Ceramidase expression facilitates membrane turnover a and endocytosis of rhodopsin in photoreceptors." Proceedings of the National Academy of Sciences of the United States of America 101(7): 1922-1926.
Acharya, U., S. Patel, et al. (2003). "Modulating sphingolipid biosynthetic pathway rescues photoreceptor degeneration." Science 299(5613): 1740-1743.
Adachi-Yamada, T., T. Gotoh, et al. (1999). "De novo synthesis of sphingolipids is required for cell survival by down-regulating c-Jun N-terminal kinase in Drosophila imaginal discs." Molecular and Cellular Biology 19(10): 7276-7286.
Adams, M. D., S. E. Celniker, et al. (2000). "The genome sequence of Drosophila melanogaster." Science 287(5461): 2185-2195.
Aerts, A. M., P. Zabrocki, et al. (2008). "Ydclp ceramidase triggers organelle fragmentation, apoptosis and accelerated ageing in yeast." Cellular and Molecular Life Sciences 65(12): 1933-1942.
Ahn, J. H., Y. G. Ko, et al. (1999). "Suppression of ceramide-mediated apoptosis by HSP70." Molecules and Cells 9(2): 200-206.
Akiyama, S. K., S. S. Yamada, et al. (1989). "Analysis of the Role of Glycosylation of the Human Fibronectin Receptor." Journal of Biological Chemistry 264(30):18011-18018.
Alessenko, A. V., V. G. Korobko, et al. (1997). "Relation of biological activity of mutant forms of recombinant human tumor necrosis factor alpha and accumulation of sphingosine in murine liver." Biochemistry and Molecular Biology International 42(1): 143-154.
Ashburner, M., C. Detwiler, et al. (1983). "The Genetics of a Small Autosomal Region of Drosophila-Melanogaster Containing the Structural Gene for Alcohol-Dehydrogenase .6. Induced Revertants of Scutoid." Genetics 104(3): 405-431.
Auge, N., M. Nikolova-Karakashian, et al. (1999). "Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase." Journal of Biological Chemistry 274(31): 21533-21538.
Beeler, T., D. Bacikova, et al. (1998). "The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2 Delta mutant." Journal of Biological Chemistry 273(46): 30688-30694.
Bernardo, K., R. Hurwitz, et al. (1995). "Purification, Characterization, and Biosynthesis of Human Acid Ceramidase." Journal of Biological Chemistry 270(19): 11098-11102.
Bieber, L. L., J. D. Oconnor, et al. (1969). "Occurrence of Tetradecasphing-4-Enine and Hexadecasphing-4-Enine as Principal Sphingosines of Musca Domestica Larvae and Adults." Biochimica Et Biophysica Acta 187(1): 157-&.
Blazquez, C, I. Galve-Roperh, et al. (2000). "De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase." Faseb Journal 14(14): 2315-2322.
Boquet, I., R. Hitier, et al. (2000). "Central brain postembryonic development in Drosophila: Implication of genes expressed at the interhemispheric junction." Journal of Neurobiology 42(1): 33-48.
Bourbon, N. A., J. Yun, et al. (2000). "Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex." Journal of Biological Chemistry 275(45): 35617-35623.
Bozcuk, A. N. (1972). "DNA-Synthesis in Absence of Somatic Cell-Division Associated with Aging in Drosophila-Subobscura." Experimental Gerontology 7(3): 147-&.
Brinkmann, U. (1998). "CAS, the human homologue of the yeast chromosome-segregation gene CSE1, in proliferation, apoptosis, and cancer." American Journal of Human Genetics 62(3): 509-513.
Buede, R., C. Rinkerschaffer, et al. (1991). "Cloning and Characterization of Lcbl, a Saccharomyces Gene Required for Biosynthesis of the Long-Chain Base Component of Sphingolipids." Journal of Bacteriology 173(14): 4325-4332.
Burek, C, J. Roth, et al. (2001). "The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells." Oncogene 20(45): 6493-6502.
Chalfant, C. E., K. Rathman, et al. (2002). "De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells - Dependence on protein phosphatase-1." Journal of Biological Chemistry 277(15): 12587-12595.
Chang, H. C, L. H. Tsai, et al. (2001). "Role of AKT kinase in sphingosine-induced apoptosis in human hepatoma cells." Journal of Cellular Physiology 188(2):188-193.
Coussin, R, R. H. Scott, et al. (2002). "Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles differential role in vasoconstriction." Circulation Research 91(2): 151-157.
Cuvillier, O., L. Edsall, et al. (2000). "Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells." Journal of Biological Chemistry 275(21): 15691-15700.
Cuvillier, O., V. E. Nava, et al. (2001). "Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells." Cell Death and Differentiation 8(2): 162-171.
Cuvillier, O., D. S. Rosenthal, et al. (1998). "Sphingosine 1-phosphate inhibits activation of caspases that cleave poly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymphocytes." Journal of Biological Chemistry 273(5): 2910-2916.
Dbaibo, G. S., M. Y. Pushkareva, et al. (1995). "Retinoblastoma Gene-Product as a Downstream Target for a Ceramide-Dependent Pathway of Growth Arrest." Proceedings of the National Academy of Sciences of the United States of America 92(5): 1347-1351.
Dennis, R. D., R. Geyer, et al. (1985). "Glycosphingolipids in Insects - Chemical Structures of Ceramide Monosaccharide, Disaccharide, and Trisaccharide from Pupae of Calliphora-Vicina (Insecta, Diptera)." European Journal of Biochemistry 146(1): 51-58.
Dennis, R. D., R. Geyer, et al. (1985). "Glycosphingolipids in Insects - Chemical Structures of Ceramide Tetrasaccharide, Pentasaccharide, Hexasaccharide, and Heptasaccharide from Calliphora-Vicina Pupae (Insecta, Diptera)." Journal of Biological Chemistry 260(9): 5370-5375.
Dickson, R. C. (2008). "New insights into sphingolipid metabolism and function in budding yeast." Journal of Lipid Research 49(5): 909-921.
Dickson, R. C. and R. L. Lester (1999). "Metabolism and selected functions of sphingolipids in the yeast Saccharomyces cerevisiae." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1438(3): 305-321.
Dickson, R. C, R. L. Lester, et al. (2000). "Serine palmitoyltransferase." Sphingolipid Metabolism and Cell Signaling, Pt A 311: 3-9.
Dickson, R. C, C. Sumanasekera, et al. (2006). "Functions and metabolism of sphingolipids in Saccharomyces cerevisiae." Progress in Lipid Research 45(6):447-465.
Dmello, N. P., A. M. Childress, et al. (1994). "Cloning and Characterization of Lagl, a Longevity-Assurance Gene in Yeast." Journal of Biological Chemistry 269(22):15451-15459.
Dolph, P. J., R. Ranganathan, et al. (1993). "Arrestin Function in Inactivation ofG-Protein Coupled Receptor Rhodopsin Invivo." Science 260(5116): 1910-1916.
Duan, R. D. (2006). "Alkaline sphingomyelinase: An old enzyme with novel implications." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1761(3): 281-291.
El Bawab, S., A. Bielawska, et al. (1999). "Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain." Journal of Biological Chemistry 274(39): 27948-27955.
El Bawab, S., P. Roddy, et al. (2000). "Molecular cloning and characterization of a human mitochondrial ceramidase." Journal of Biological Chemistry 275(28):21508-21513.
Eliyahu, E., J. H. Park, et al. (2007). "Acid ceramidase is a novel factor required for early embryo survival." Faseb Journal 21(7): 1403-1409.
Elojeimy, S., X. Liu, et al. (2007). "Role of acid ceramidase in resistance to FasL: Therapeutic approaches based on acid ceramidase inhibitors and FasL gene therapy." Molecular Therapy 15(7): 1259-1263.
Elsen, L., R. Betz, et al. (2002). "Identification of ceramide binding proteins in neuronal cells: A critical point of view." Neurochemical Research 27(7-8):717-727.
English, D., J. G. N. Garcia, et al. (2001). "Platelet-released phospholipids link haemostasis and angiogenesis." Cardiovascular Research 49(3): 588-599.
Franzen, R., A. Pautz, et al. (2001). "Interleukin-1 beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells." Journal of Biological Chemistry 276(38): 35382-35389.
Fujita, Y., E. Ohama, et al. (2006). "Fragmentation of Golgi apparatus of nigral neurons with alpha-synuclein-positive inclusions in patients with Parkinson's disease." Acta Neuropathologica 112(3): 261-265.
Funato, K., R. Lombardi, et al. (2003). "Lcb4p is a key regulator of ceramide synthesis from exogenous long chain sphingoid base in Saccharomyces cerevisiae." Journal of Biological Chemistry 278(9): 7325-7334.
Futerman, A. H. and Y. A. Hannun (2004), "The complex life of simple sphingolipids." Embo Reports 5(8): 777-782.
Futerman, A. H. and H. Riezman (2005). "The ins and outs of sphingolipid synthesis." Trends in Cell Biology 15(6): 312-318.
Fyrst, H., D. R. Herr, et al. (2004). "Characterization of free endogenous C-14 and C-16 sphingoid bases from Drosophila melanogaster." Journal of Lipid Research 45(1): 54-62.
Galve-Roperh, I., D. Rueda, et al. (2002). "Mechanism of extracellular signal-regulated kinase activation by the CB1 cannabinoid receptor." Molecular Pharmacology 62(6): 1385-1392.
Gatt, S. (1963). "Enzymic Hydrolysis and Synthesis of Ceramides." Journal of Biological Chemistry 238(9): 3131-&.
Goetzl, E. J., W. G. Wang, et al. (2007). "Sphingosine 1-phosphate as an intracellular messenger and extracellular mediator in immunity." Acta Paediatrica 96: 49-52.
Goni, F. M. and A. Alonso (2002). "Sphingomyelinases: enzymology and membrane activity." Febs Letters 531(1): 38-46.
Hanada, K. (2003). "Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1632(1-2): 16-30.
Hanada, K., T. Hara, et al. (1998). "Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin - Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase." Journal of Biological Chemistry 273(50): 33787-33794.
Hanada, K., K. Kumagai, et al. (2003). "Molecular machinery for non-vesicular trafficking of ceramide." Nature 426(6968): 803-809.
Hannun, Y. A. and R. M. Bell (1989). "Regulation of Protein Kinase-C by Sphingosine and Lysosphingolipids." Clinica Chimica Acta 185(3): 333-346.
Hannun, Y. A. and C. Luberto (2004). "Lipid metabolism: Ceramide transfer protein adds a new dimension." Current Biology 14(4): R163-R165.
Hannun, Y. A. and L. M. Obeid (1997). "Mechanisms of ceramide-mediated apoptosis." Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury 3 407: 145-149.
Hara, S., S. Nakashima, et al. (2004). "p53-independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis." Cell Death and Differentiation 11(8): 853-861.
He, X. X., N. Okino, et al. (2003). "Purification and characterization of recombinant, human acid ceramidase - Catalytic reactions and interactions with acid sphingomyelinase." Journal of Biological Chemistry 278(35): 32978-32986.
Helfand, S. L. and B. Rogina (2003). "Molecular genetics of aging in the fly: is this the end of the beginning?" Bioessays 25(2): 134-141.
Herr, D. R., H. Fyrst, et al. (2004). "Characterization of the Drosophila sphingosinekinases and requirement for Sk2 in normal reproductive function." Journal of Biological Chemistry 279(13): 12685-12694.
Herr, D. R., H. Fyrst, et al. (2003). "Sply regulation of sphingolipid signaling molecules is essential for Drosophila development." Development 130(11):2443-2453.
Hildenbr.Gr, T. Abraham, et al. (1971). "Metabolism of Ceramide Phosphorylethanolamine, Phosphatidylinositol, Phosphatidylserine and Phosphatidylglycerol by Housefly Larvae." Lipids 6(7): 508-&.
Hla, T. (2003). "Signaling and biological actions of sphingosine 1-phosphate." Pharmacological Research 47(5): 401-407.
Hoekstra, D., O. Maier, et al. (2003). "Membrane dynamics and cell polarity: the role of sphingolipids." Journal of Lipid Research 44(5): 869-877.
Holthuis, J. C. M., T. Pomorski, et al. (2001). "The organizing potential of sphingolipids in intracellular membrane transport." Physiological Reviews 81(4):1689-1723.
Holzenberger, M., J. Dupont, et al. (2003). "IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice." Nature 421(6919): 182-187.
Houben, E., W. M. Holleran, et al. (2006). "Differentiation-associated expression of ceramidase isoforms in cultured keratinocytes and epidermis." Journal of Lipid Research 47(5): 1063-1070.
Hu, W., R. J. Xu, et al. (2005). "Golgi fragmentation is associated with ceramide-induced cellular effects." Molecular Biology of the Cell 16(3):1555-1567.
Huwiler, A., J. Brunner, et al. (1996). "Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase." Proceedings of the National Academy of Sciences of the United States of America 93(14):6959-6963.
Huwiler, A., T. Kolter, et al. (2000). "Physiology and pathophysiology of sphingolipid metabolism and signaling." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1485(2-3): 63-99.
Igarashi, Y., S. Hakomori, et al. (1989). "Effect of Chemically Well-Defined Sphingosine and Its N-Methyl Derivatives on Protein Kinase-C and Src Kinase-Activities." Biochemistry 28(17): 6796-6800.
Ikeda, H., Y. Yatomi, et al. (2000). "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells (vol 279, pg G304, 2000)." American Journal of Physiology-Gastrointestinal and Liver Physiology 279(5):U1-U1.
Ito, K. and Y. Hotta (1992). "Proliferation Pattern of Postembryonic Neuroblasts in the Brain of Drosophila-Melanogaster." Developmental Biology 149(1): 134-148.
Jarvis, W. D., F. A. Fornari, et al. (1997). "Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine." Molecular Pharmacology 52(6): 935-947.
Jefferson, A. B. and H. Schulman (1988). "Sphingosine Inhibits Calmodulin-Dependent Enzymes." Journal of Biological Chemistry 263(30):15241-15244.
Kagedal, K., M. Zhao, et al. (2001). "Sphingosine-induced apoptosis is dependent on lysosomal proteases." Biochemical Journal 359: 335-343.
Kango-Singh, M. and G. Haider (2004). "Drosophila as an emerging model to study metastasis." Genome Biology 5(4): -.
Karim, F. D., H. C. Chang, et al. (1996). "A screen for genes that function downstream of Rasl during Drosophila eye development." Genetics 143(1):315-329.
Katsuma, S., Y. Hada, et al. (2002). "Signalling mechanisms in sphingosine 1-phosphate-promoted mesangial cell proliferation." Genes to Cells 7(12):1217-1230.
Kellokumpu, S., R. Sormunen, et al. (2002). "Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH." Febs Letters 516(1-3): 217-224.
Kernan, M, D. Cowan, et al. (1994). "Genetic Dissection of Mechanosensory Transduction - Mechanoreception-Defective Mutations of Drosophila." Neuron 12(6): 1195-1206.
Kim, D. S., S. Y. Kim, et al. (2004). "Sphingosine-1-phosphate inhibits human keratinocyte proliferation via Akt/protein kinase B inactivation." Cellular Signalling 16(1): 89-95.
Kim, L. T., S. Ishihara, et al. (1992). "Altered Glycosylation and Cell-Surface Expression of Beta-1 Integrin Receptors during Keratinocyte Activation." Journal of Cell Science 103: 743-753.
Kim, S., 1. Hong, et al. (2006). "Phytosphingosine stimulates the differentiation of human keratinocytes and inhibits TPA-induced inflammatory epidermal hyperplasia in hairless mouse skin." Molecular Medicine 12(1-3): 17-24.
Kluk, M. J. and T. Hla (2001). "Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration." Circulation Research 89(6): 496-502.
Kohno, M., M. Momoi, et al. (2006). "Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation." Molecular and Cellular Biology 26(19): 7211-7223.
Kolter, T., R. L. Proia, et al. (2002). "Combinatorial ganglioside biosynthesis." Journal of Biological Chemistry 277(29): 25859-25862.
Kono, M., J. L. Dreier, et al. (2006). "Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids." Journal of Biological Chemistry 281(11): 7324-7331.
Kowald, A. and T. B. L. Kirkwood (1994). "Towards a Network Theory of Aging - a Model Combining the Free-Radical Theory and the Protein Error Theory." Journal of Theoretical Biology 168(1): 75-94.
Krown, K. A., M. T. Page, et al. (1996). "Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes - Involvement of the sphingolipid signaling cascade in cardiac cell death." Journal of Clinical Investigation 98(12):2854-2865.
Lee, J. Y., Y A. Hannun, et al. (1996). "Ceramide inactivates cellular protein kinase C alpha." Journal of Biological Chemistry 271(22): 13169-13174.
Lee, M. J., S. Thangada, et al. (1999). "Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate." Cell 99(3):301-312.
Lepine, S., B. Lakatos, et al. (2004). "Sphingosine contributes to glucocorticoid-induced apoptosis of thymocytes independently of the mitochondrial pathway." Journal of Immunology 173(6): 3783-3790.
Lepine, S., B. Lakatos, et al. (2002). "Involvement of sphingosine in dexamethasone-induced thymocyte apoptosis." Cell Signaling, Transcription, and Translation as Therapeutic Targets 973: 190-193.
Li, C. M., J. H. Park, et al. (2002). "Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes (vol 79, pg 218, 2002)." Genomics 79(6): 890-890.
Li, G. C, H. Alexander, et al. (2000). "Molecular basis for resistance to the anticancer drug cisplatin in Dictyostelium." Microbiology-Uk 146: 2219-2227.
Li, G. C, C. Foote, et al. (2001). "Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum." Development 128(18):3473-3483.
Libera, L. D., R. Sabbadini, et al. (2001). "Apoptosis in the skeletal muscle of rats with heart failure is associated with increased serum levels of TNF-alpha and sphingosine." Journal of Molecular and Cellular Cardiology 33(10): 1871-1878.
Liu, Y. J., R. Wada, et al. (2000). "Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation." Journal of Clinical Investigation 106(8): 951-961.
Lu, F. G. and C. S. Wong (2004). "Radiation-induced apoptosis of oligodendrocytes and its association with increased ceramide and down-regulated protein kinase B/Akt activity." International Journal of Radiation Biology 80(1): 39-51.
Mao, C. G. and L. M. Obeid (2008). "Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1781(9): 424-434.
Mao, C. G, R. J. Xu, et al. (2000). "Cloning of an alkaline ceramidase from Saccharomyces cerevisiae - An enzyme with reverse (CoA-independent) ceramide synthase activity." Journal of Biological Chemistry 275(10):6876-6884.
Mao, C. G., R. J. Xu, et al. (2000). "Cloning and characterization of a Saccharomyces cerevisiae alkaline ceramidase with specificity for dihydroceramide." Journal of Biological Chemistry 275(40): 31369-31378.
Mao, C. G, R. J. Xu, et al. (2001). "Cloning and characterization of a novel human alkaline ceramidase - A mammalian enzyme that hydrolyzes phytoceramide." Journal of Biological Chemistry 276(28): 26577-26588.
Mao, C. G, R. J. Xu, et al. (2003). "Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase - An enzyme that preferentially regulates metabolism of very long chain ceramides." Journal of Biological Chemistry 278(33): 31184-31191.
Mattie, M., G. Brooker, et al. (1994). "Sphingosine-1-Phosphate, a Putative 2nd Messenger, Mobilizes Calcium from Internal Stores Via an Inositol Trisphosphate-Independent Pathway." Journal of Biological Chemistry 269(5):3181-3188.
Megidish, T., J. Cooper, et al. (1998). "A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein." Journal of Biological Chemistry 273(34): 21834-21845.
Menaldino, D. S., A. Bushnev, et al. (2003). "Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action." Pharmacological Research 47(5): 373-381.
Merrill, A. H. (2002). "De novo sphingolipid biosynthesis: A necessary, but dangerous, pathway." Journal of Biological Chemistry 277(29): 25843-25846.
Merrill, A. H., E. M. Schmelz, et al. (1997). "Sphingolipids - The enigmatic lipid class: Biochemistry, physiology, and pathophysiology." Toxicology and Applied Pharmacology 142(1): 208-225.
Michaud, N. R., M. Therrien, et al. (1997). "KSR stimulates Raf-1 activity in a kinase-independent manner." Proceedings of the National Academy of Sciences of the United States of America 94(24): 12792-12796.
Mizugishi, K., C. L. Li, et al. (2007). "Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice." Journal of Clinical Investigation 117(10): 2993-3006.
Mizugishi, K., T. Yamashita, et al. (2005). "Essential role for sphingosine kinases in neural and vascular development." Molecular and Cellular Biology 25(24):11113-11121.
Mizutani, Y., A. Kihara, et al. (2004). "Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation." Febs Letters 563(1-3): 93-97.
Momoi, T., Y. Benyoseph, et al. (1982). "Substrate-Specificities of Acid and Alkaline Ceramidases in Fibroblasts from Patients with Farber Disease and Controls." Biochemical Journal 205(2): 419-425.
Monick, M. M., R. K. Mallampalli, et al. (2004). "Cooperative prosurvival activity by ERK and Akt in human alveolar macrophages is dependent on high levels of acid ceramidase activity." Journal of Immunology 173(1): 123-135.
Morales, A., R. Paris, et al. (2007). "Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo." Oncogene 26(6): 905-916.
Muller, G, P. Storz, et al. (1998). "Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling." Embo Journal 17(3): 732-742.
Nagahara, Y., T. Shinomiya, et al. (2005). "Phytosphingosine induced mitochondria-involved apoptosis." Cancer Science 96(2): 83-92.
Nussleinvolhard, C. and E. Wieschaus (1980). "Mutations Affecting Segment Number and Polarity in Drosophila." Nature 287(5785): 795-801.
Obeid, L. A., Y. Okamoto, et al. (2002). "Yeast sphingolipids: metabolism and biology." Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids 1585(2-3): 163-171.
Ohlsson, L., C. Palmberg, et al. (2007). "Purification and characterization of human intestinal neutral ceramidase." Naunyn-Schmiedebergs Archives of Pharmacology 374(4): 329-330.
Ohta, H., E. A. Sweeney, et al. (1995). "Induction of Apoptosis by Sphingosine in Human Leukemic H1-60 Cells - a Possible Endogenous Modulator of Apoptotic DNA Fragmentation Occurring during Phorbol Ester-Induced Differentiation." Cancer Research 55(3): 691-697.
Okino, N., S. Ichinose, et al. (1999). "Molecular cloning, sequencing, and expression of the gene encoding alkaline ceramidase from Pseudomonas aeruginosa. Cloning of a ceramidase homologue from Mycobacterium tuberculosis." J Biol Chem 274(51): 36616-22.
Okino, N., M. Tani, et al. (1998). "Purification and characterization of a novel ceramidase from Pseudomonas aeruginosa." Journal of Biological Chemistry 273(23): 14368-14373.
Olivera, A., T. Kohama, et al. (1999). "Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival." Journal of Cell Biology 147(3): 545-557.
Olsson, M., R. D. Duan, et al. (2004). "Rat intestinal ceramidase: purification, properties, and physiological relevance." American Journal of Physiology-Gastrointestinal and Liver Physiology 287(4): G929-G937.
Osawa, Y., H. Uchinami, et al. (2005). "Roles for C-16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha." Journal of Biological Chemistry 280(30): 27879-27887.
Paik, J. H., S. S. Chae, et al. (2001). "Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha(v)beta(3)- and beta(1)-containing integrins." Journal of Biological Chemistry 276(15): 11830-11837.
Pelagalli, A., M. A. Belisario, et al. (1999). "The mycotoxin fumonisin Bl inhibits integrin-mediated cell-matrix adhesion." Biochimie 81(10): 1003-1008.
Pelled, D., T. Raveh, et al. (2002). "Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons." Journal of Biological Chemistry 277(3): 1957-1961.
Phan, V. H., D. R. Herr, et al. (2007). "Disruption of sphingolipid metabolism elicits apoptosis-associated reproductive defects in Drosophila." Developmental Biology 309(2): 329-341.
Powers, R. W., M. Kaeberlein, et al. (2006). "Extension of chronological life span in yeast by decreased TOR pathway signaling." Genes & Development 20(2):174-184.
Rao, R. P., C. Yuan, et al. (2007). "Ceramide transfer protein function is essential for normal oxidative stress response and lifespan." Proceedings of the National Academy of Sciences of the United States of America 104(27): 11364-11369.
Renault, A. D., M. Starz-Gaiano, et al. (2002). "Metabolism of sphingosine 1-phosphate and lysophosphatidic acid: a genome wide analysis of gene expression in Drosophila." Mechanisms of Development 119: S293-S301.
Riebeling, C, J. C. Allegood, et al. (2003). "Two mammalian longevity assurance gene (LAG1) family members, trh 1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors." Journal of Biological Chemistry 278(44): 43452-43459.
Rietveld, A., S. Neutz, et al. (1999). "Association of sterol- and glycosylphosphatidylinositol-linked proteins with Drosophila raft lipid microdomains." Journal of Biological Chemistry 274(17): 12049-12054.
Riezman, H. and G. van Meer (2004). "Lipid pickup and delivery." Nature Cell Biology 6(1): 15-16.
Roccamo, A. M, M. F. Pediconi, et al. (1999). "Cells defective in sphingolipids biosynthesis express low amounts of muscle nicotinic acetylcholine receptor." European Journal of Neuroscience 11(5): 1615-1623.
Rong, Y. S. (2002). "Gene targeting by homologous recombination: a powerful addition to the genetic arsenal for Drosophila geneticists." Biochemical and Biophysical Research Communications 297(1): 1-5.
Rubin, G. M, M. D. Yandell, et al. (2000). "Comparative genomics of the eukaryotes." Science 287(5461): 2204-2215.
Ruvolo, P. P. (2003). "Intracellular signal transduction pathways activated by ceramide and its metabolites." Pharmacological Research 47(5): 383-392.
Ruvolo, P. P., X. M. Deng, et al. (1999). "Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A." Journal of Biological Chemistry 274(29): 20296-20300.
Ruvolo, P. P., F. Q. Gao, et al. (2001). "Ceramide regulates protein synthesis by a novel mechanism involving the cellular PKR activator RAX." Journal of Biological Chemistry 276(15): 11754-11758.
Saad, A. F., W. D. Meacham, et al. (2007). "The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy." Cancer Biology & Therapy 6(9): 1455-1460.
Saba, J. D. and T. Hla (2004). "Point-counterpoint of sphingosine 1-phosphate metabolism." Circulation Research 94(6): 724-734.
Sakagami, H. and H. Kondo (1997). "Molecular cloning and developmental expression of a rat homoiogue of death-associated protein kinase in the nervous system." Molecular Brain Research 52(2): 249-256.
Samet, D. and Y. Barenholz (1999). "Characterization of acidic and neutral sphingomyelinase activities in crude extracts of HL-60 cells." Chemistry and Physics of Lipids 102(1-2): 65-77.
Schmelz, E. M., P. C. Roberts, et al. (2001). "Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids." Cancer Research 61(18): 6723-6729.
Schutze, S., M. Wickel, et al. (2000). "Use of affinity chromatography and TID-ceramide photoaffinity labeling for detection of ceramide-binding proteins." Sphingolipid Metabolism and Cell Signaling, Pt B 312: 429-438.
Schwientek, T., B. Keck, et al. (2002). "The Drosophila gene brainiac encodes a glycosyltransferase putatively involved in glycosphingolipid synthesis." Journal of Biological Chemistry 277(36): 32421-32429.
Segui, B., C. Bezombes, et al. (2000). "Stress-induced apoptosis is not mediated by endolysosomal ceramide." Faseb Journal 14(1): 36-47.
Sekizawa, Y, T. Kubo, et al. (1997). "Molecular cloning of cDNA for lysenin, a novel protein in the earthworm Eisenia foetida that causes contraction of rat vascular smooth muscle." Gene 191(1): 97-102.
Seppo, A., M. Moreland, et al. (2000). "Zwitterionic and acidic glycosphingolipids of the Drosophila melanogaster embryo." European Journal of Biochemistry 267(12): 3549-3558.
Seppo, A. and M. Tiemeyer (2000). "Function and structure of Drosophila glycans." Glycobiology 10(8): 751-760.
Shayman, J. A. (2000). "Sphingolipids." Kidney International 58(1): 11-26. Shin, J., H. Lee, et al. (2007). "Sphingosine 1-phosphate triggers apoptotic signal for B16 melanoma cells via prolonged ERK and caspase-8 activation." Journal of Investigative Dermatology 127: S96-S96.
Shirakabe, K., K. Yamaguchi, et al. (1997). "TAK1 mediates the ceramide signaling to stress-activated protein kinase c-Jun N-terminal kinase." Journal of Biological Chemistry 272(13): 8141-8144.
Solomon, J. C, K. Sharma, et al. (2003). "A novel role for sphingolipid intermediates in activation-induced cell death in T cells." Cell Death and Differentiation 10(2):193-202.
Spradling, A. C, D. Stern, et al. (1999). "The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital drosophila genes." Genetics 153(1): 135-177.
Stapleton, M., G. C. Liao, et al. (2002). "The Drosophila gene collection: Identification of putative full-length cDNAs for 70% of D-melanogaster genes." Genome Research 12(8): 1294-1300.
Stieber, A., J. O. Gonatas, et al. (2004). "Disruption of the structure of the Golgi apparatus and the function of the secretory pathway by mutants G93A and G85R of Cu, Zn superoxide dismutase (SOD1) of familial amyotrophic lateral sclerosis." Journal of the Neurological Sciences 219(1-2): 45-53.
Stieber, A., Z. Mourelatos, et al. (1996). "In Alzheimer's disease the golgi apparatus of a population of neurons without neurofibrillary tangles is fragmented and atrophic." American Journal of Pathology 148(2): 415-426.
Stoica, B. A., V. A. Movsesyan, et al. (2003). "Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3 beta, and induction of the mitochondrial-dependent intrinsic caspase pathway." Molecular and Cellular Neuroscience 22(3): 365-382.
Strelow, A., K. Bernardo, et al. (2000). "Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death." Journal of Experimental Medicine 192(5): 601-611.
Sugita, M., M. Williams, et al. (1975). "Ceramidase and Ceramide Synthesis in Human Kidney and Cerebellum - Description of a New Alkaline Ceramidase." Biochimica Et Biophysica Acta 398(1): 125-131.
Sugiura, M., K. Kono, et al. (2002). "Ceramide kinase, a novel lipid kinase - Molecular cloning and functional characterization." Journal of Biological Chemistry 277(26): 23294-23300.
Sun, W., R. J. Xu, et al. (2008). "Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes." Journal of Investigative Dermatology 128(2): 389-397.
Suzuki, E., K. Handa, et al. (2004). "Sphingosine-dependent apoptosis: A unified concept based on multiple mechanisms operating in concert." Proceedings of the National Academy of Sciences of the United States of America 101(41):14788-14793.
Sweeney, E. A., C. Sakakura, et al. (1996). "Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines." International Journal of Cancer 66(3): 358-366.
Tani, M., Y. Igarashi, et al. (2005). "Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu." Journal of Biological Chemistry 280(44): 36592-36600.
Tani, M., N. Okino, et al. (2000). "Purification and characterization of a neutral ceramidase from mouse liver - A single protein catalyzes the reversible reaction in which ceramide is both hydrolyzed and synthesized." Journal of Biological Chemistry 275(5): 3462-3468.
Tani, M, N. Okino, et al. (2000). "Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase - A novel but highly conserved gene family of neutral/alkaline ceramidases." Journal of Biological Chemistry 275(15):11229-11234.
Tanimoto, T., Z. G. Jin, et al. (2002). "Transactivation of vascular endothelial growth factor (VEGF) receptor FIK-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS)." Journal of Biological Chemistry 277(45): 42997-43001.
Tapon, N. (2003). "Modeling transformation and metastasis in Drosophila." Cancer Cell 4(5): 333-335.
Tatar, M., A. Bartke, et al. (2003). "The endocrine regulation of aging by insulin-like signals." Science 299(5611): 1346-1351.
Tenenbaum, D. (2003). "What's all the buzz? Fruit flies provide unique model for cancer research." Journal of the National Cancer Institute 95(23): 1742-1744.
Thon, L., H. Mohlig, et al. (2005). "Ceramide mediates caspase-independent programmed cell death." Faseb Journal 19(14): 1945-1956.
Van Brocklyn, J. R., C. A. Letterle, et al. (2002). "Sphingosine-1-phosphate stimulates human glioma cell proliferation through G(i)-coupled receptors: role of ERK MAP kinase and phosphatidylinositol 3-kinase beta." Cancer Letters 181(2):195-204.
Wandall, H. H., J. W. Pedersen, et al. (2003). "Drosophila egghead encodes beta 1,4-mannosyltransferase predicted to form the immediate precursor glycosphingolipid substrate for brainiac." Journal of Biological Chemistry 278(3):1411-1414.
Wayne, M. L. and L. M. Mclntyre (2002). "Combining mapping and arraying: An approach to candidate gene identification." Proceedings of the National Academy of Sciences of the United States of America 99(23): 14903-14906.
Wells, G. B. and R. L. Lester (1983). "The Isolation and Characterization of a Mutant Strain of Saccharomyces-Cerevisiae That Requires a Long-Chain Base for Growth and for Synthesis of Phosphosphingolipids." Journal of Biological Chemistry 258(17): 200-203.
Williams, R. D., E. Wang, et al. (1984). "Enzymology of Long-Chain Base Synthesis by Liver - Characterization of Serine Palmitoyltransferase in Rat-Liver Microsomes." Archives of Biochemistry and Biophysics 228(1): 282-291.
Xu, R. J., J. F. Jin, et al. (2006). "Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and SIP." Faseb Journal 20(11):1813-1825.
Yamaoka, S., M. Miyaji, et al. (2004). "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells." Journal of Biological Chemistry 279(18):18688-18693.
Yang, S. N. (2000). "Ceramide-induced sustained depression of synaptic currents mediated by ionotropic glutamate receptors in the hippocampus: An essential role of postsynaptic protein phosphatases." Neuroscience 96(2): 253-258.
Yoshimura, Y., N. Okino, et al. (2002). "Molecular cloning and characterization of a secretory neutral ceramidase of Drosophila melanogaster." Journal ofBiochemistry 132(2): 229-236.
Yoshimura, Y, M. Tani, et al. (2004). "Molecular cloning and functional analysis of zebrafish neutral ceramidase." Journal of Biological Chemistry 279(42):44012-44022.
Zhang, H., N. N. Desai, et al. (1991). "Sphingosine-1-Phosphate, a Novel Lipid, Involved in Cellular Proliferation." Journal of Cell Biology 114(1): 155-167.
Zhang, Y. H., B. Yao, et al. (1997). "Kinase suppressor of Ras is ceramide-activated protein kinase." Cell 89(1): 63-72.
Zhou, H. L., S. K. Summers, et al. (1998). "Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis." Journal of Biological Chemistry 273(26): 16568-16575.