Advances in the Signal Transduction of Ceramide and Related Sphingolipids

References

• Merrill AH Jr., Schmelz EM, Dillehay DL, et al., Sphingolipids — the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharm 1997; 142: 208–25.
   PubMed Web of Science ®Google Scholar
• Olaisson H, Mardh S Arvidson G. Phospholipid organization in H,K-ATPase-containing membranes from pig gastric mucosa. J Biol Chem 1985; 260: 11262–7.
   Google Scholar
• Rawyler A, van der Schaft PH, Roelofsen B, et al. Phospholipid localization in the plasma membrane of Friend erythroleukemic cells and mouse erythrocytes. Biochemistry 1985; 24: 1777–83.
   Google Scholar
• Bartolf M, Franson RC. Characterization and localization of neutral sphingomyelinase in bovine adrenal medulla. J Lipid Res 1986; 27: 57–63.
   Google Scholar
• Hise MK, Mantulin WW Weinman EJ. Fatty acyl chain composition in the determination of renal membrane order. J Clin Invest 1986; 77: 768–73.
   Google Scholar
• Kolesnick RN, Clegg S. 1,2-Diacylglycerols, but not phorbol esters, activate a potential inhibitory pathway for protein kinase C in GH3 pituitary cells. Evidence for involvement of a sphingomyelinase. J Biol Chem 1988; 263: 6534–7.
   Google Scholar
• Mathias S, Dressler KA Kolesnick RN. Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci USA 1991; 88: 10009–13.
   PubMedGoogle Scholar
• Dobrowsky RT, Hannun YA. Ceramide stimulates a cytosolic protein phosphatase. J Biol Chem 1992; 267: 5048–51.
   PubMed Web of Science ®Google Scholar
• Merrill AH Jr, Lingrell S, Wang E, et al. Sphingolipid biosynthesis de novo by rat hepatocytes in culture. Ceramide and sphingomyelin are associated with, but not required for, very low density lipoprotein secretion. J Biol Chem 1995; 270:</b>13834-41.
   Google Scholar
• Ballou LR, Laulederkind SJ, Rosloniec EF, et al. Ceramide signalling and the immune response. Biochim Biophys Acta 1996; 1301: 273–87.
   PubMedGoogle Scholar
• Brindley DN, Abousalham A, Kikuchi Y, et al. “Cross talk” between the bioactive glycerolipids and sphingolipids in signal transduction. Biochem Cell Biol 1996; 74: 469–76.
   Google Scholar
• Paumen MB, Ishida Y, Muramatsu M, et al. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 1997; 272: 3324–9.
   PubMed Web of Science ®Google Scholar
• Kolesnick RN, Krönke M. Regulation of ceramide production and apoptosis. Annu Rev Physiol 1998; 60: 643–65.
   PubMed Web of Science ®Google Scholar
• Hirschberg K, Rodger J Futerman AH. The long-chain sphingoid base of sphingolipids is acylated at the cytosolic surface of the endoplasmic reticulum in rat liver. Biochem J 1993; 290: 751–7.
   Google Scholar
• Ridgway ND. 25-Hydroxycholesterol stimulates sphingomyelin synthesis in Chinese hamster ovary cells. J Lipid Res 1995; 36: 1345–58.
   Google Scholar
• Kok JW, Nikolova-Karakashian M, Klappe K, et al. Dihydroceramide biology. Structure-specific metabolism and intracellular localization. J Biol Chem 1997; 272: 21128–36.
   Google Scholar
• Merrill AH, Liotta DC Riley RE. Bioactive properties of sphingosine and structurally related compounds. In: Bell RM et al. ed. Handbook of lipid research V and lipid second messenger. p. 205–237. New York: Plenum Press, 1996.
   Google Scholar
• Heape AM, Boiron F, Bessoule JJ, et al. Peripheral nerve sphingomyelin and cerebroside are both formed via two metabolically and kinetically distinct pathways in vivo. Eur J Biochem 1994; 226: 491–504.
   Google Scholar
• Quinn P, Allan D. Two separate pools of sphingomyelin in BHK cells. Biochim Biophys Acta 1992; 1124: 95–100.
   Google Scholar
• Kallen KJ, Quinn P Allan D. Monensin inhibits synthesis of plasma membrane sphingomyelin by blocking transport of ceramide through the Golgi: evidence for two sites of sphingomyelin synthesis in BHK cells. Biochim Biophys Acta 1993; 1166: 305–8.
   Google Scholar
• Borchardt RA, Lee WT, Kalen A, et al. Growth-dependent regulation of cellular ceramides in human T-cells. Biochim Biophys Acta 1994; 1212: 327–36.
   Google Scholar
• Fitzgerald V, Blank ML Snyder F. Molecular species of sphingomyelin in sphingomyelinase-sensitive and sphingomyelinase-resistant pools of HL-60 cells. Lipids 1995; 30: 805–9.
   Google Scholar
• Kwon G, Bohrer A, Han X, et al. Characterization of the sphingomyelin content of isolated pancreatic islets. Evaluation of the role of sphingomyelin hydrolysis in the action of interleukin-1 to induce islet overproduction of nitric oxide. Biochim Biophys Acta 1996; 1300: 63–72.
   Google Scholar
• Peña LA, Fuks Z Kolesnick R. Stress-induced apoptosis and the sphingomyelin pathway. Biochem Pharmacol 1997; 53: 615–21.
   PubMed Web of Science ®Google Scholar
• Taga S, Carlier K, Mishal Z, et al. Intracellular signaling events in CD77-mediated apoptosis of Burkitt’s lymphoma cells. Blood 1997; 90: 2757–67.
   PubMedGoogle Scholar
• Kolesnick R. 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res 1998; 58: 2260–4.
   Google Scholar
• Meacci E, Vasta V, Farnararo M, et al. Bradykinin increases ceramide and sphingosine content in human fibroblasts: possible involvement of glycosphingolipids. Biochem Biophys Res Commun 1996; 221: 1–7.
   Google Scholar
• Michel C, van Echten-Deckert G, Rother J, et al. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 1997; 272: 22432–7.
   PubMed Web of Science ®Google Scholar
• Ghosh S, Strum JC Bell RM. Lipid biochemistry: function of glycerolipids and sphingolipids in cellular signaling. FASEB 1997; 11: 45–50.
   PubMed Web of Science ®Google Scholar
• Liu B, Obeid LM Hannun YA. Sphingomyelinases in cell regulation. Semin Cell Dev Biol 1997; 311–22.
   Google Scholar
• Liu B, Andrieu-Abadie N, Levade T, et al. Hannun YA. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem 1998; 273: 11313–20.
   PubMed Web of Science ®Google Scholar
• Cifone MG, Roncaioli P, De Maria R, et al. Testi R. Multiple pathways originate at the Fas/ APO-1 (CD95) receptor: sequential involvement of phosphatidylcholine-specific phospholi-pase C and acidic sphingomyelinase in the propagation of the apoptotic signal. EMBO J 1995; 14: 5859–68.
   PubMed Web of Science ®Google Scholar
• Schütze S, Machleidt T Kronke M. The role of diacylglycerol and ceramide in tumor necrosis factor and interleukin-1 signal transduction. J Leuk Biol 1994; 56: 533–41.
   PubMed Web of Science ®Google Scholar
• Jayadev S, Hayter HL, Andrieu N, et al. Phospholipase A2 is necessary for tumor necrosis factor alpha-induced ceramide generation in L929 cells. J Biol Chem 1997; 272: 17196–203.
   PubMedGoogle Scholar
• Fanani ML, Maggio B. Mutual modulation of sphingomyelinase and phospholipase A2 activities against mixed lipid monolayers by their lipid intermediates and glycosphingolipids. Mol Membr Biol 1997; 14: 25–9.
   Web of Science ®Google Scholar
• Schissel SL, Tweedie-Hardman J, Rapp JH, et al. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J Clin Invest 1996; 98: 1455–64.
   PubMed Web of Science ®Google Scholar
• Zhang P, Liu B, Jenkins GM, et al. Expression of neutral sphingomyelinase identifies a distinct pool of sphingomyelin involved in apoptosis. J Biol Chem 1997; 272: 9609–12.
   PubMedGoogle Scholar
• Chen J, Nikolova-Karakashian M, Merrill AH Jr, et al. Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes. J Biol Chem 1995; 270: 25233–8.
   PubMed Web of Science ®Google Scholar
• Dobrowsky RT, Werner MH, Castellino AM, et al. Hannun YA. Activation of the sphingo-myelin cycle through the low-affinity neurotrophin receptor. Science 1994; 265: 1596–9.
   Google Scholar
• Yanaga F, Watson SP. Ceramide does not mediate the effect of tumour necrosis factor alpha on superoxide generation in human neutrophils. Biochem J 1994; 298: 733–8.
   Google Scholar
• Simon CG Jr, Chatterjee S Gear AR. Sphingomyelinase activity in human platelets. Thromb Res 1998; 90: 155–61.
   PubMed Web of Science ®Google Scholar
• Schissel SL, Keesler GA, Schuchman EH, et al. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem 1998; 273: 18250–9.
   Google Scholar
• Field FJ, Chen H, Born E, et al. Release of ceramide after membrane sphingomyelin hydrolysis decreases the basolateral secretion of triacylglycerol and apolipoprotein B in cultured human intestinal cells. J Clin Invest 1993; 92: 2609–19.
   Google Scholar
• Raines MA, Kolesnick RN Golde DW. Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells. J Biol Chem 1993; 268: 14572–5.
   PubMedGoogle Scholar
• Olivera A, Romanowski A, Rani CS, et al. Differential effects of sphingomyelinase and cell-permeable ceramide analogs on proliferation of Swiss 3T3 fibroblasts. Biochim Biophys Acta 1997; 1348: 311–23.
   Google Scholar
• Higuchi M, Singh S, Jaffrezou JP, et al. Acidic sphingomyelinase-generated ceramide is needed but not sufficient for TNF-induced apoptosis and nuclear factor-kappa B activation. J Immunol 1996; 157: 297–304.
   Google Scholar
• Lee JY, Leonhardt LG Obeid LM. Cell-cycle-dependent changes in ceramide levels preceding retinoblastoma protein dephosphorylation in G2/M. Biochem J 1998; 334: 457–61.
   Google Scholar
• Xu J, Yeh CH, Chen S, et al. Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death. J Biol Chem 1998; 273: 16521–6.
   PubMedGoogle Scholar
• Ohanian J, Liu G, Ohanian V, et al. Lipid second messengers derived from glycerolipids and sphingolipids, and their role in smooth muscle function. Acta Physiol Scand 1998; 164: 533–548.
   Google Scholar
• Luberto C, Hannun YA. Sphingomyelin synthase, a potential regulator of intracellular levels of ceramide and diacylglycerol during SV40 transformation. Does sphingomyelin synthase account for the putative phosphatidylcholine-specific phospholipase C? J Biol Chem 1998; 273: 14550–9.
   Google Scholar
• Schütze S, Wiegmann K, Machleidt T, et al. TNF-induced activation of NF-kappa B. Immunobiology 1995; 193: 193–203.
   Google Scholar
• Jabbar SA, Hoffbrand AV Wickremasinghe RG. Defects in signal transduction pathways in chronic B lymphocytic leukemia cells. Leuk Lymph 1995; 18: 163–70.
   PubMed Web of Science ®Google Scholar
• Yada Y, Higuchi K Imokawa G. Purification and biochemical characterization of membrane-bound epidermal ceramidases from guinea pig skin. J Biol Chem 1995; 270: 12677–84.
   Google Scholar
• Boiron-Sargueil F, Heape A, Garbay B, et al. Cerebroside formation in the peripheral nervous system of normal and Trembler mice. Neurosci Lett 1995; 186: 21–4.
   Google Scholar
• Cifone MG, De Maria R, Roncaioli P, et al. Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J Exp Med 1994; 180: 1547–52.
   PubMed Web of Science ®Google Scholar
• Sjoholm A. Ceramide inhibits pancreatic beta-cell insulin production and mitogenesis and mimics the actions of interleukin-1 beta. FEBS Lett 1995; 367: 283–6.
   PubMedGoogle Scholar
• Kanety H, Hemi R, Papa MZ, et al. Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. J Biol Chem 1996; 271: 9895–7.
   PubMedGoogle Scholar
• Brogi A, Strazza M, Melli M, et al. Induction of intracellular ceramide by interleukin-1 beta in oligodendrocytes. J Cell Biochem 1997; 66: 532–41.
   Google Scholar
• Komori H, Ito M. Conversion of short-chain ceramides to short-chain ceramide GM3 in B16 melanoma cells. FEBS Lett 1995; 374: 299–302.
   Google Scholar
• Bielawska A, Greenberg MS, Perry D, et al. (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidase. J Biol Chem 1996; 271: 12646–54.
   PubMed Web of Science ®Google Scholar
• Wiesner DA, Dawson G. Staurosporine induces programmed cell death in embryonic neurons and activation of the ceramide pathway. J Neurochem 1996; 66: 1418–25.
   PubMedGoogle Scholar
• Okino N, Tani M, Imayama S, et al. Purification and characterization of a novel ceramidase from Pseudomonas aeruginosa. J Biol Chem 1998; 273: 14368–73.
   PubMedGoogle Scholar
• Mathias S, Peña LA Kolesnick RN. Signal transduction of stress via ceramide. Biochem J 1998; 335: 465–80.
   PubMed Web of Science ®Google Scholar
• Shimeno H, Soeda S, Sakamoto M, et al. Partial purification and characterization of sphin-gosine N-acyltransferase(ceramide synthase) from bovine liver mitochondrion-rich fraction. Lipids 1998; 33: 601–5.
   Google Scholar
• Tsunoda M, Sharma RP Riley RT. Early fumonisin B1 toxicity in relation to disrupted sphingolipid metabolism in male BALB/c mice. J Biochem Mol Toxicol 1998; 12: 281–9.
   PubMedGoogle Scholar
• Humpf HU, Schmelz EM, Meredith FL, et al. Acylation of naturally occurring and synthetic 1-deoxysphinganines by ceramide synthase. Formation of N-palmitoyl-aminopentol produces a toxic metabolite of hydrolyzed fumonisin, AP1, and a new category of ceramide synthase inhibitor. J Biol Chem 1998; 273: 19060–4.
   PubMed Web of Science ®Google Scholar
• Ueda N, Kaushal GP, Hong X, et al. Role of enhanced ceramide generation in DNA damage and cell death in chemical hypoxic injury to LLC-PK1 cells. Kidney Int 1998; 54: 399–406.
   PubMed Web of Science ®Google Scholar
• Lochhead KM, Zager RA. Fluorinated anesthetic exposure “activates” the renal cortical sphingomyelinase cascade. Kidney Int 1998; 54: 373–81.
   Google Scholar
• Yokoyama K, Nojiri H, Suzuki M, et al. Clear differences in ceramide metabolism between glycosphingolipids and sphingomyelin in a human promyelocytic leukemia cell line HL-60 stimulated by a differentiation inducer. FEBS Lett 1995; 368: 477–80.
   Google Scholar
• Shinghal R, Scheller RH Bajjalieh SM. Ceramide 1-phosphate phosphatase activity in brain. J Neurochem 1993; 61: 2279–85.
   Google Scholar
• Mathias S, Younes A, Kan CC, et al. Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta. Science 1993; 259: 519–22.
   PubMed Web of Science ®Google Scholar
• Haimovitz-Friedman A, Kan CC, Ehleiter D, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994; 180: 525–35.
   PubMed Web of Science ®Google Scholar
• Chmura SJ, Mauceri HJ, Advani S, et al. Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation. Cancer Res 1997; 57: 4340–7.
   PubMedGoogle Scholar
• Strum JC, Small GW, Pauig SB, et al. 1-beta-D-Arabinofuranosylcytosine stimulates ceramide and diglyceride formation in HL-60 cells. J Biol Chem 1994; 269: 15493–7.
   PubMed Web of Science ®Google Scholar
• Liu G, Kleine L, Nasrallah R, et al. Bradykinin inhibits ceramide production and activates phospholipase D in rabbit RCCD cells. Am J Phys 1999; 276: F589–598.
   Google Scholar
• Gomez-Munoz A, Waggoner DW, O’Brien L, et al. Interaction of ceramides, sphingosine, and sphingosine 1-phosphate in regulating DNA synthesis and phospholipase D activity. J Biol Chem 1995; 270: 26318–25.
   PubMed Web of Science ®Google Scholar
• Ji L, Zhang G Hirabayashi Y. Inhibition of tumor necrosis factor alpha- and ceramide-induced internucleosomal DNA fragmentation by herbimycin A in U937 cells. Biochem Biophys Res Commun 1995; 212: 640–7.
   Google Scholar
• Viani P, Zini I, Cervato G, et al. Effect of endothelin-1 induced ischemia on peroxidative damage and membrane properties in rat striatum synaptosomes. Neurochem Res 1995; 20: 689–95.
   PubMed Web of Science ®Google Scholar
• Wright HM, Malik KU. Prostacyclin formation elicited by endothelin-1 in rat aorta is mediated via phospholipase D activation and not phospholipase C or A2. Circ Res 1996; 79: 271–6.
   Google Scholar
• Catalan RE, Aragones MD Martinez AM, et al. Involvement of sphingolipids in the endothelin-1 signal transduction mechanism in rat brain. Neurosci Lett 1996; 220: 121–4.
   Google Scholar
• Geilen CC, Bektas M, Wieder T, et al. The vitamin D3 analogue, calcipotriol, induces sphingomyelin hydrolysis in human keratinocytes. FEBS Lett 1996; 378: 88–92.
   PubMed Web of Science ®Google Scholar
• Linardic CM, Jayadev S Hannun YA. Activation of the sphingomyelin cycle by brefeldin A: effects of brefeldin A on differentiation and implications for a role for ceramide in regulation of protein trafficking. Cell Growth Differ 1996; 7: 765–74.
   Google Scholar
• Hedlund M, Svensson M, Nilsson A, et al. Role of the ceramide-signaling pathway in cytokine responses to P-fimbriated Escherichia coli. J Exp Med 1996; 183: 1037–44.
   Google Scholar
• Clejan S, Dotson RS, Wolf EW, et al. Morphological differentiation of N1E-115 neuroblas-toma cells by dimethyl sulfoxide activation of lipid second messengers. Exp Cell Res 1996; 224: 16–27.
   Google Scholar
• Sillence DJ, Allan D. Evidence against an early signalling role for ceramide in Fas-mediated apoptosis. Biochem J 1997; 324: 29–32.
   PubMedGoogle Scholar
• Kinscherf R, Claus R, Deigner HP, et al. Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human mac-rophages. FEBS Lett 1997; 405: 55–9.
   PubMedGoogle Scholar
• Wiesner DA, Kilkus JP, Gottschalk AR, et al. Anti-immunoglobulin-induced apoptosis in WEHI 231 cells involves the slow formation of ceramide from sphingomyelin and is blocked by bcl-XL. J Biol Chem 1997; 272: 9868–76.
   Google Scholar
• Sbrissa D, Yamada H, Hajra A, et al. Bombesin-stimulated ceramide production and MAP kinase activation in rabbit rectosigmoid smooth muscle cells. Am J Phys 1997; 272: G1615–25.
   Google Scholar
• Visnjic D, Batinic D Banfic H. Arachidonic acid mediates interferon-gamma-induced sphin-gomyelin hydrolysis and monocytic marker expression in HL-60 cell line. Blood 1997; 89: 81–91.
   PubMed Web of Science ®Google Scholar
• Brenner B, Grassme HU, Muller C, et al. L-selectin stimulates the neutral sphingomyelinase and induces release of ceramide. Exp Cell Res 1998; 243: 123–8.
   PubMed Web of Science ®Google Scholar
• Cabot MC, Han TY Giuliano AE. The multidrug resistance modulator SDZ PSC 833 is a potent activator of cellular ceramide formation. FEBS Lett 1998; 431: 185–8.
   Google Scholar
• Separovic D, Mann KJ Oleinick NL. Association of ceramide accumulation with photody-namic treatment-induced cell death. Photochem Photobiol 1998; 68: 101–9.
   PubMedGoogle Scholar
• Gamen S, Hanson DA, Kaspar A, et al. Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways. J Immunol 1998; 161: 1758–64.
   PubMed Web of Science ®Google Scholar
• Suy S, Mitchell JB, Ehleiter D, et al. Nitroxides tempol and tempo induce divergent signal transduction pathways in MDA-MB 231 breast cancer cells. J Biol Chem 1998; 273: 17871–8.
   Google Scholar
• Galve-Roperh I, Sanchez C, Segui B, et al. Evidence for the lack of involvement of sphingo-myelin hydrolysis in the tumor necrosis factor-induced secretion of nerve growth factor in primary astrocyte cultures. J Neurochem 1998; 71: 498–505.
   Google Scholar
• Gerritsen ME, Shen CP Perry CA. Synovial fibroblasts and the sphingomyelinase pathway: sphingomyelin turnover and ceramide generation are not signaling mechanisms for the actions of tumor necrosis factor-alpha. Am J Pathol 1998; 152: 505–12.
   PubMed Web of Science ®Google Scholar
• Allan-Yorke J, Record M, de Preval C, et al. Distinct pathways for tumor necrosis factor alpha and ceramides in human cytomegalovirus infection. J Virol 1998; 72: 2316–22.
   Google Scholar
• Casaccia-Bonnefil P, Carter BD, Dobrowsky RT, et al. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996; 383: 716–9.
   PubMed Web of Science ®Google Scholar
• Haddad EB, Rousell J, Lindsay MA, et al. Synergy between tumor necrosis factor alpha and interleukin 1beta in inducing transcriptional down-regulation of muscarinic M2 receptor gene expression. Involvement of protein kinase A and ceramide pathways. J Biol Chem 1996; 271: 32586–92.
   PubMed Web of Science ®Google Scholar
• Wiegmann K, Schütze S, Machleidt T, et al. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 1994; 78: 1005–15.
   PubMed Web of Science ®Google Scholar
• Brenner B, Koppenhoefer U, Weinstock C, et al. Fas-or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem 1997; 272: 22173–81.
   PubMed Web of Science ®Google Scholar
• Bilderback TR, Grigsby RJ Dobrowsky RT. Association of p75(NTR) with caveolin and localization of neurotrophin-induced sphingomyelin hydrolysis to caveolae. J Biol Chem 1997; 272: 10922–7.
   PubMed Web of Science ®Google Scholar
• Monney L, Olivier R, Otter I, et al. Role of an acidic compartment in tumor-necrosis-factor-alpha-induced production of ceramide, activation of caspase-3 and apoptosis. Eur J Biochem 1998; 251: 295–303.
   PubMedGoogle Scholar
• Tollefson AE, Hermiston TW, Lichtenstein DL, et al. Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 1998; 392: 726–30.
   PubMedGoogle Scholar
• Anderson RG, Kamen BA, Rothberg KG, et al. Potocytosis: sequestration and transport of small molecules by caveolae. Science 1992; 255: 410–1.
   PubMed Web of Science ®Google Scholar
• Liu P, Anderson RG. Compartmentalized production of ceramide at the cell surface. J Biol Chem 1993; 90: 10909–13.
   Google Scholar
• Okamoto T, Schlegel A, Scherer PE, et al. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem 1998; 273: 5419–22.
   PubMed Web of Science ®Google Scholar
• Teixeira A, Chaverot N, Schroder C, et al. Requirement of caveolae microdomains in extracellular signal-regulated kinase and focal adhesion kinase activation induced by endothelin-1 in primary astrocytes. J Neurochem 1999; 72: 120–8.
   PubMed Web of Science ®Google Scholar
• Lobie PE, Sadir R, Graichen R, et al. Caveolar internalization of growth hormone. Exp Cell Res 1999; 246: 47–55.
   Google Scholar
• Smart EJ, Ying YS Anderson RG. Hormonal regulation of caveolae internalization. J Cell Biol 1995; 131: 929–38.
   PubMedGoogle Scholar
• Goldkorn T, Dressler KA, Muindi J, et al. Ceramide stimulates epidermal growth factor receptor phosphoryla-tion in A431 human epidermoid carcinoma cells. Evidence that ceramide may mediate sphingosine action. J Biol Chem 1991; 266: 16092–7.
   PubMed Web of Science ®Google Scholar
• Joseph CK, Byun HS, Bittman R, et al. Substrate recognition by ceramide-activated protein kinase. Evidence that kinase activity is proline-directed. J Biol Chem 1993; 268: 20002–6.
   PubMedGoogle Scholar
• Liu J, Mathias S, Yang Z, et al. Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase. J Biol Chem 1994; 269: 3047–52.
   PubMedGoogle Scholar
• Nickels JT, Broach JR. A ceramide-activated protein phosphatase mediates ceramide-induced G1 arrest of Saccharomyces cerevisiae. Gene Dev 1996; 10: 382–94.
   Google Scholar
• Wolff RA, Dobrowsky RT, Bielawska A, et al. Role of ceramide-activated protein phos-phatase in ceramide-mediated signal transduction. J Biol Chem 1994; 269: 19605–9.
   PubMedGoogle Scholar
• Reyes JG, Robayna IG, Delgado PS, et al. Galarreta CMR. c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells. J Biol Chem 1996; 271: 21375–80.
   Google Scholar
• Prinetti A, Bassi R, Riboni L, et al. Involvement of a ceramide activated protein phosphatase in the differentiation of neuroblastoma Neuro2a cells. FEBS Lett 1997; 414: 475–9.
   Google Scholar
• Fishbein JD, Dobrowsky RT, Bielawska A, et al. Ceramide-mediated growth inhibition and CAPP are conserved in Saccharomyces cerevisiae. J Biol Chem 1993; 268: 9255–61.
   Google Scholar
• Dobrowsky RT, Kamibayashi C, Mumby MC, et al. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 1993; 268: 15523–30.
   PubMed Web of Science ®Google Scholar
• Wong K, Li XB, Hunchuk N. N-acetylsphingosine (C2-ceramide) inhibited neutrophil super-oxide formation and calcium influx. J Biol Chem 1995; 270: 3056–62.
   Google Scholar
• Begum N, Ragolia L Srinivasan M. Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells. Eur J Biochem 1996; 238: 214–20.
   PubMedGoogle Scholar
• Galadari S, Kishikawa K, Kamibayashi C, et al. Purification and characterization of ceramide-activated protein phosphatases. Biochemistry 1998; 37: 11232–8.
   PubMed Web of Science ®Google Scholar
• Campbell SL, Khosravi-Far R, Rossman KL, et al. Increasing complexity of Ras signaling. Oncogene 1998; 17: 1395–1413.
   PubMed Web of Science ®Google Scholar
• Dhanasekaran N, Tsim ST, Dermott JM, et al. Regulation of cell proliferation by G proteins. Oncogene 1998; 17: 1383–94.
   PubMed Web of Science ®Google Scholar
• Dhanasekaran N, Premkumar Reddy E. Signaling by dual specificity kinases. Oncogene 1998; 17: 1447–55.
   PubMed Web of Science ®Google Scholar
• Modur V, Zimmerman GA, Prescott SM, et al. Endothelial cell inflammatory responses to tumor necrosis factor alpha. Ceramide-dependent and independent mitogen-activated protein kinase cascades. J Biol Chem 1996; 271: 13094–102.
   PubMed Web of Science ®Google Scholar
• Huwiler A, Brunner J, Hummel R, et al. Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc Natl Acad Sci USA 1996; 93: 6959–63.
   PubMedGoogle Scholar
• Belka C, Wiegmann K, Adam D, et al. Tumor necrosis factor (TNF)-alpha activates c-raf-1 kinase via the p55 TNF receptor engaging neutral sphingomyelinase. EMBO J 1995; 14: 1156–65.
   PubMedGoogle Scholar
• Gulbins E, Bissonnette R, Mahboubi A, et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 1995; 2: 341–51.
   PubMed Web of Science ®Google Scholar
• Gulbins E, Coggeshall KM, Brenner B, et al. Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway. J Biol Chem 1996; 271: 26389–94.
   PubMedGoogle Scholar
• Sasaki T, Hazeki K, Hazeki O, et al. Permissive effect of ceramide on growth factor-induced cell proliferation. Biochem J 1995; 311: 829–34.
   Google Scholar
• Westwick JK, Bielawska AE, Dbaibo G, et al. Ceramide activates the stress-activated protein kinases. J Biol Chem 1995; 270: 22689–92.
   PubMed Web of Science ®Google Scholar
• Suchard SJ, Mansfield PJ, Boxer LA, et al. Mitogen-activated protein kinase activation during IgG-dependent phagocytosis in human neutrophils: inhibition by ceramide. J Immunol 1997; 158: 4961–7.
   Google Scholar
• Yao B, Zhang Y, Delikat S, et al. Phosphorylation of Raf by ceramide-activated protein kinase. Nature 1995; 378: 307–10.
   PubMed Web of Science ®Google Scholar
• Basu S, Bayoumy S, Zhang Y, et al. BAD enables ceramide to signal apoptosis via Ras and Raf-1. J Biol Chem 1998; 273: 30419–26.
   PubMedGoogle Scholar
• Zhang Y, Yao B, Delikat S, et al. Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 1997; 89: 63–72.
   PubMed Web of Science ®Google Scholar
• Westwick JK, Weitzel C, Minden A, et al. Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem 1994; 269: 26396–401.
   PubMed Web of Science ®Google Scholar
• Winston BW, Lange-Carter CA, Gardner AM, et al. Tumor necrosis factor alpha rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages. Proc Natl Acad Sci USA 1995; 92: 1614–8.
   PubMed Web of Science ®Google Scholar
• Gardner AM, Johnson GL. Fibroblast growth factor-2 suppression of tumor necrosis factor alpha-mediated apoptosis requires Ras and the activation of mitogen-activated protein kinase. J Biol Chem 1996; 271: 14560–6.
   PubMed Web of Science ®Google Scholar
• Muller G, Storz P, Bourteele S, et al. Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling. EMBO J 1998; 17: 732–42.
   PubMedGoogle Scholar
• Kyriakis JM, Banerjee P, Nikolakaki E, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 1994; 369: 156–60.
   PubMed Web of Science ®Google Scholar
• Derijard B, Hibi M, Wu IH, et al. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994; 76(6): 1025–37.
   Google Scholar
• Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biology 1997; 9: 180–6.
   PubMed Web of Science ®Google Scholar
• Basu S, Kolesnick R. Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 1998; 17: 3277–85.
   PubMed Web of Science ®Google Scholar
• Verheij M, Ruiter GA, Zerp SF, et al. The role of the stress-activated protein kinase (SAPK/ JNK) signaling pathway in radiation-induced apoptosis. Radiother Oncol 1998; 47: 225–32.
   PubMed Web of Science ®Google Scholar
• Verheij M, Bose R, Lin XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996; 380: 75–9.
   PubMed Web of Science ®Google Scholar
• Coroneos E, Wang Y, Panuska JR, et al. Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades. Biochem J 1996; 316: 13–7.
   PubMedGoogle Scholar
• Cuvillier O, Pirianov G, Kleuser B, et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996; 381: 800–3.
   PubMed Web of Science ®Google Scholar
• Pyne S, Chapman J, Steele L, et al. Sphingomyelin-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle. Eur J Biochem 1996; 237: 819–26.
   PubMedGoogle Scholar
• Jayadev S, Liu B, Bielawska AE, et al. Role for ceramide in cell cycle arrest. J Biol Chem 1995; 270: 2047–52.
   PubMed Web of Science ®Google Scholar
• Jarvis WD, Kolesnick RN, Fornari FA, et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci USA 1994; 91: 73–7.
   PubMed Web of Science ®Google Scholar
• Obeid LM, Linardic CM, Karolak LA, et al. Programmed cell death induced by ceramide. Science 1993; 259: 1769–71.
   PubMed Web of Science ®Google Scholar
• Zhang P, Miller BS, Rosenzweig SA, et al. Activation of C-jun N-terminal kinase/stress-activated protein kinase in primary glial cultures. J Neurosci Res 1996; 46: 114–21.
   Google Scholar
• Yamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995; 270: 2008–11.
   PubMed Web of Science ®Google Scholar
• Reunanen N, Westermarck J, Hakkinen L, et al. Enhancement of fibroblast collagenase (matrix metalloproteinase-1) gene expression by ceramide is mediated by extracellular signal-regulated and stress-activated protein kinase pathways. J Biol Chem 1998; 273: 5137–45.
   PubMed Web of Science ®Google Scholar
• Scheid MP, Foltz IN, Young PR, et al. Ceramide and cyclic adenosine monophosphate (cAMP) induce cAMP response element binding protein phosphorylation via distinct signaling pathways while having opposite effects on myeloid cell survival. Blood 1999; 93: 217–25.
   PubMedGoogle Scholar
• Subbaramaiah K, Chung WJ, Dannenberg AJ. Ceramide regulates the transcription of cyclooxygenase-2. Evidence for involvement of extracellular signal-regulated kinase/c-Jun N-terminal kinase and p38 mitogen-activated protein kinase pathways. J Biol Chem 1998; 273: 32943–9.
   PubMed Web of Science ®Google Scholar
• Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270: 1326–31.
   PubMed Web of Science ®Google Scholar
• Toyoshima F, Moriguchi T Nishida E. Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases. J Cell Biol 1997; 139: 1005–15.
   PubMed Web of Science ®Google Scholar
• Ludwig S, Engel K, Hoffmeyer A, et al. 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways. Mol Cell Biol 1996; 16: 6687–97.
   PubMed Web of Science ®Google Scholar
• Gutkind JS. Cell growth control by G protein-coupled receptors: from signal transduction to signal integration. Oncogene 1998; 17: 1331–42.
   PubMed Web of Science ®Google Scholar
• Ragg SJ, Kaga S, Berg KA, et al. The mitogen-activated protein kinase pathway inhibits ceramide-induced terminal differentiation of a human monoblastic leukemia cell line, U937. J Immunol 1998; 161: 1390–8.
   Google Scholar
• Hayakawa M, Jayadev S, Tsujimoto M, et al. Role of ceramide in stimulation of the transcription of cytosolic phospholipase A2 and cyclooxygenase 2. Biochem Biophys Res Co 1996; 220: 681–6.
   PubMed Web of Science ®Google Scholar
• Kirtikara K, Laulederkind SJ, Raghow R, et al. An accessory role for ceramide in interleukin-1beta induced prostaglandin synthesis. Mol Cell Biochem 1998; 181: 41–8.
   PubMedGoogle Scholar
• Hashizume T, Kageura T Sato T. Different effects of cell-permeable ceramide analogs on platelet activation. Biochem Mol Biol Int 1998; 44: 489–96.
   Google Scholar
• Sato T, Kageura T, Hashizume T, et al. Stimulation by ceramide of phospholipase A2 activation through a mechanism related to the phospholipase C-initiated signaling pathway in rabbit platelets. J Biochem 1999; 125: 96–102.
   PubMed Web of Science ®Google Scholar
• Huang HW, Goldberg EM Zidovetzki R. Ceramide induces structural defects into phosphati-dylcholine bilayers and activates phospholipase A2. Biochem Biophys Res Co 1996; 220: 834–8.
   Google Scholar
• Muller G, Ayoub M, Storz P, et al. PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. EMBO J 1995; 14: 1961–9.
   PubMedGoogle Scholar
• Abe A, Shayman JA. Purification and characterization of 1-O-acylceramide synthase, a novel phospholipase A2 with transacylase activity. J Biol Chem 1998; 273: 8467–74.
   PubMed Web of Science ®Google Scholar
• Abe A, Shayman JA Radin NS. A novel enzyme that catalyzes the esterification of N-acetylsphingosine. Metabolism of C2-ceramides. J Biol Chem 1996; 271: 14383–9.
   PubMedGoogle Scholar
• Gomez-Munoz A, Martin A, O’Brien L, et al. Cell-permeable ceramides inhibit the stimulation of DNA synthesis and phospholipase D activity by phosphatidate and lysophosphatidate in rat fibroblasts. J Biol Chem 1994; 269: 8937–43.
   PubMed Web of Science ®Google Scholar
• Yoshimura S, Sakai H, Ohguchi K, et al. Changes in the activity and mRNA levels of phospholipase D during ceramide-induced apoptosis in rat C6 glial cells. J Neurochem 1997; 69: 713–20.
   PubMed Web of Science ®Google Scholar
• Nakamura Y, Nakashima S, Ojio K, et al. Ceramide inhibits IgE-mediated activation of phospholipase D, but not of phospholipase C, in rat basophilic leukemia (RBL-2H3) cells. J Immunol 1996; 156: 256–62.
   PubMedGoogle Scholar
• Exton JH. New developments in phospholipase D. J Biol Chem 1997; 272: 15579–82.
   PubMedGoogle Scholar
• Lacal JC. Regulation of proliferation and apoptosis by Ras and Rho GTPases through specific phospholipid-dependent signaling. FEBS Lett 1997; 410: 73–7.
   Google Scholar
• del Peso L, Lucas L, Esteve P, et al. Activation of phospholipase D by growth factors and oncogenes in murine fibroblasts follow alternative but cross-talking pathways. Biochem J 1997; 322: 519–28.
   PubMedGoogle Scholar
• Martin A, Brown FD, Hodgkin MN, et al. Activation of phospholipase D and phosphatidylinositol 4-phosphate 5-kinase in HL60 membranes is mediated by endogenous Arf but not Rho. J Biol Chem 1996; 271: 17397–403.
   PubMedGoogle Scholar
• Heller RA, Kronke M. Tumor necrosis factor receptor-mediated signaling pathways. J Cell Biol 1994; 126: 5–9.
   PubMed Web of Science ®Google Scholar
• Nakamura T, Abe A, Balazovich KJ, et al. Ceramide regulates oxidant release in adherent human neutrophils. J Biol Chem 1994; 269: 18384–9.
   PubMed Web of Science ®Google Scholar
• Younes A, Kahn DW, Besterman JM, et al. Ceramide is a competitive inhibitor of diacylglycerol kinase in vitro and in intact human leukemia (HL-60) cells. J Biol Chem 1992; 267: 842–7.
   Google Scholar
• Venable ME, Blobe GC Obeid LM. Identification of a defect in the phospholipase D/ diacylglycerol pathway in cellular senescence. J Biol Chem 1994; 269: 26040–4.
   PubMed Web of Science ®Google Scholar
• Venable ME, Bielawska A Obeid LM. Ceramide inhibits phospholipase D in a cell-free system. J Biol Chem 1996; 271: 24800–5.
   PubMedGoogle Scholar
• Jones MJ, Murray AW. Evidence that ceramide selectively inhibits protein kinase C-alpha translocation and modulates bradykinin activation of phospholipase D. J Biol Chem 1995; 270: 5007–13.
   PubMed Web of Science ®Google Scholar
• Abousalham A, Liossis C, O’Brien L, et al. Cell-permeable ceramides prevent the activation of phospholipase D by ADP-ribosylation factor and RhoA. J Biol Chem 1997; 272: 1069–75.
   PubMed Web of Science ®Google Scholar
• Esteve P, del Peso L Lacal JC. Induction of apoptosis by rho in NIH 3T3 cells requires two complementary signals. Ceramides function as a progression factor for apoptosis. Oncogene 1995; 11: 2657–65.
   PubMedGoogle Scholar
• Esteve P, Embade N, Perona R, et al. Rho-regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but Bcl2 dependent pathway. Oncogene 1998; 17: 1855–69.
   PubMed Web of Science ®Google Scholar
• van Helvoort A, van’t Hof W, Ritsema T, et al. Conversion of diacylglycerol to phosphatidyl-choline on the basolateral surface of epithelial (Madin-Darby canine kidney) cells. Evidence for the reverse action of a sphingomyelin synthase. J Biol Chem 1994; 269: 1763–9.
   PubMed Web of Science ®Google Scholar
• Kolesnick RN, Paley AE. 1,2-Diacylglycerols and phorbol esters stimulate phosphatidylcho-line metabolism in GH3 pituitary cells. Evidence for separate mechanisms of action. J Biol Chem 1987; 262: 9204–10.
   PubMedGoogle Scholar
• Schütze S, Potthoff K, Machleidt T, et al. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 1992; 71: 765–76.
   PubMed Web of Science ®Google Scholar
• Lozano J, Berra E, Municio MM, et al. Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J Biol Chem 1994; 269: 19200–2.
   PubMed Web of Science ®Google Scholar
• Adam D, Ruff A, Strelow A, et al. Induction of stress-activated protein kinases/c-Jun N-terminal kinases by the p55 tumour necrosis factor receptor does not require sphingomyelinases. Biochem J 1998; 333: 343–50.
   Google Scholar
• Machleidt T, Wiegmann K, Henkel T, et al. Sphingomyelinase activates proteolytic I kappa B-alpha degradation in a cell-free system. J Biol Chem 1994; 269: 13760–5.
   PubMed Web of Science ®Google Scholar
• Lee JY, Hannun YA Obeid LM. Ceramide inactivates cellular protein kinase C alpha. J Biol Chem 1996; 271: 13169–74.
   PubMed Web of Science ®Google Scholar
• Tanabe F, Cui SH Ito M. Ceramide promotes calpain-mediated proteolysis of protein kinase C beta in murine polymorphonuclear leukocytes. Biochem Bioph Res Co 1998; 242: 129–33.
   PubMed Web of Science ®Google Scholar
• Sawai H, Okazaki T, Takeda Y, et al. Ceramide-induced translocation of protein kinase C-delta and epsilon to the cytosol. Implications in apoptosis. J Biol Chem 1997; 272: 2452–8.
   PubMedGoogle Scholar
• Galve-Roperh I, Haro A Diaz-Laviada I. Ceramide-induced translocation of protein kinase C zeta in primary cultures of astrocytes. FEBS Lett 1997; 415: 271–4.
   PubMedGoogle Scholar
• Diaz-Meco MT, Dominguez I, Sanz L, et al. z PKC induces phosphorylation and inactivation of I kappa B-alpha in vitro. EMBO J 1994; 13: 2842–8.
   PubMed Web of Science ®Google Scholar
• Kelly ML, Tang Y, Rosensweig N, et al. Granulocyte-macrophage colony-stimulating factor rescues TF-1 leukemia cells from ionizing radiation-induced apoptosis through a pathway mediated by protein kinase Calpha. Blood 1998; 92: 416–24.
   Google Scholar
• Zegers MMP, Hoekstra D. Sphingolipid transport to the apical plasma membrane domain in human hepatoma cells is controlled by PKC and PKA activity: a correlation with cell polarity in HepG2 cells. J Cell Biol 1997; 138: 307–21.
   Google Scholar
• Pahan K, Sheikh FG, Khan M, et al. Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem 1998; 273: 2591–600.
   Google Scholar
• Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141–79.
   PubMed Web of Science ®Google Scholar
• Hatanaka Y, Fujii J, Fukutomi T, et al. Reactive oxygen species enhances the induction of inducible nitric oxide synthase by sphingomyelinase in RAW264.7 cells. Biochim Biophys Acta 1998; 1393: 203–10.
   Google Scholar
• Shimabukuro M, Zhou YT, Levi M, et al. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 1998; 95: 2498–502.
   PubMed Web of Science ®Google Scholar
• Sciorati C, Rovere P, Ferrarini M, et al. Clementi E. Autocrine nitric oxide modulates CD95-induced apoptosis in gamma delta T lymphocytes. J Biol Chem 1997; 272: 23211–5.
   PubMed Web of Science ®Google Scholar
• Hebestreit H, Dibbert B, Balatti I, et al. Disruption of fas receptor signaling by nitric oxide in eosinophils. J Exp Med 1998; 187: 415–25.
   PubMed Web of Science ®Google Scholar
• Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–30.
   PubMed Web of Science ®Google Scholar
• Dbaibo GS, Pushkareva MY, Jayadev S, et al. Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA 1995; 92: 1347–51.
   PubMed Web of Science ®Google Scholar
• Venable ME, Lee JY, Smyth MJ, et al. Role of ceramide in cellular senescence. J Biol Chem 1995; 270: 30701–8.
   PubMed Web of Science ®Google Scholar
• Zhang J, Alter N, Reed JC, et al. Bcl-2 interrupts the ceramide-mediated pathway of cell death. Proc Natl Acad Sci USA 1996; 93: 5325–8.
   PubMed Web of Science ®Google Scholar
• Spinedi A, Amendola A, Di Bartolomeo S, et al. Ceramide-induced apoptosis is mediated by caspase activation independently from retinoblastoma protein post-translational modification. Biochem Biophys Res Commun 1998; 243: 852–7.
   Google Scholar
• Bowen C, Spiegel S Gelmann EP. Radiation-induced apoptosis mediated by retinoblastoma protein. Cancer Res 1998; 58: 3275–81.
   Google Scholar
• McConkey DJ, Goodrich D, Bucana C, et al. The human retinoblastoma gene product suppresses ceramide-induced apoptosis in human bladder tumor cells. Oncogene 1996; 13: 1693–700.
   Google Scholar
• Oliverio S, Amendola A, Di Sano F, et al. Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis. Mol Cell Biol 1997; 17: 6040–8.
   PubMedGoogle Scholar
• Sawai H, Okazaki T Domae N. Ceramide: a lipid mediator of apoptotic signal transduction. Nippon Rinsho-Japanese J Clin Med 1996; 54: 1803–8.
   Google Scholar
• Zhao Y, Nichols JE, Valdez R, et al. Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol Endocrinol 1996; 10: 1350–7.
   PubMed Web of Science ®Google Scholar
• Welsh N. Interleukin-1 beta-induced ceramide and diacylglycerol generation may lead to activation of the c-Jun NH2-terminal kinase and the transcription factor ATF2 in the insulin-producing cell line RINm5F. J Biol Chem 1996; 271: 8307–12.
   PubMedGoogle Scholar
• Gupta S, Campbell D, Derijard B, et al. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 1995; 267: 389–93.
   PubMed Web of Science ®Google Scholar
• Yang Z, Costanzo M, Golde DW, et al. Tumor necrosis factor activation of the sphingomyelin pathway signals nuclear factor kappa B translocation in intact HL-60 cells. J Biol Chem 1993; 268: 20520–3.
   PubMed Web of Science ®Google Scholar
• Dbaibo GS, Obeid LM Hannun YA. Tumor necrosis factor-alpha (TNF-a) signal transduction through ceramide. Dissociation of growth inhibitory effects of TNFa from activation of nuclear factor-kappa B. J Biol Chem 1993; 268: 17762–6.
   PubMed Web of Science ®Google Scholar
• Singh S, Aggarwal BB. Protein-tyrosine phosphatase inhibitors block tumor necrosis factor-dependent activation of the nuclear transcription factor NF-kB. J Biol Chem 1995; 270: 10631–9.
   PubMed Web of Science ®Google Scholar
• Betts JC, Agranoff AB, Nabel GJ, et al. Dissociation of endogenous cellular ceramide from NF-kB activation. J Biol Chem 1994; 269: 8455–8.
   PubMed Web of Science ®Google Scholar
• Johns LD, Sarr T Ranges GE. Inhibition of ceramide pathway does not affect ability of TNF-a to activate nuclear factor-kappa B. J Immunol 1994; 152: 5877–82.
   PubMed Web of Science ®Google Scholar
• Kim BC, Kim JH. Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway. Biochem J 1998; 330: 1009–14.
   Google Scholar
• Nagata S. Apoptosis by death factor. Cell 1997; 88: 355–65.
   PubMed Web of Science ®Google Scholar
• Nagata S, Golstein P. The Fas death factor. Science 1995; 267: 1449–56.
   PubMed Web of Science ®Google Scholar
• Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281: 1305–8.
   PubMed Web of Science ®Google Scholar
• Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today 1992; 13: 151–3.
   PubMedGoogle Scholar
• Vandenabeele P, Declercq W, Vanhaesebroeck B, et al. Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells. J Immunol 1995; 154: 2904–13.
   PubMed Web of Science ®Google Scholar
• Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw 1996; 7: 93–124.
   PubMed Web of Science ®Google Scholar
• Tartaglia LA, Ayres TM, Wong GH, et al. A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993; 74: 845–53.
   PubMed Web of Science ®Google Scholar
• Itoh N, Nagata S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 1993; 268: 10932–7.
   PubMed Web of Science ®Google Scholar
• Hsu H, Xiong J Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995; 81: 495–504.
   PubMed Web of Science ®Google Scholar
• Chinnaiyan AM, O’Rourke K, Tewari M, et al. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995; 81: 505–12.
   PubMed Web of Science ®Google Scholar
• Boldin MP, Varfolomeev EE, Pancer Z, et al. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 1995; 270: 7795–8.
   PubMed Web of Science ®Google Scholar
• Yeh WC, Pompa JL, McCurrach ME, et al. FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 1998; 279: 1954–8.
   PubMed Web of Science ®Google Scholar
• Varfolomeev EE, Boldin MP, Goncharov TM, et al. A potential mechanism of “cross-talk” between the p55 tumor necrosis factor receptor and Fas/APO1: proteins binding to the death domains of the two receptors also bind to each other. J Exp Med 1996; 183: 1271–5.
   PubMed Web of Science ®Google Scholar
• Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996; 85: 817–27.
   PubMed Web of Science ®Google Scholar
• Fernandes-Alnemri T, Armstrong RC, Krebs J, et al. In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci USA 1996; 93: 7464–9.
   PubMed Web of Science ®Google Scholar
• Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci 1997; 22: 299–306.
   PubMed Web of Science ®Google Scholar
• Nunez G, Benedict MA, Hu Y, et al. Caspases: the proteases of the apoptotic pathway. Oncogene 1998; 17: 3237–45.
   PubMed Web of Science ®Google Scholar
• Boldin MP, Goncharov TM, Goltsev YV, et al. Involvement of MACH, a novel MORT1/ FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 1996; 85: 803–15.
   PubMed Web of Science ®Google Scholar
• Medema JP, Scaffidi C, Kischkel FC, et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 1997; 16: 2794–804.
   PubMed Web of Science ®Google Scholar
• Scaffidi C, Medema JP, Krammer PH, et al. FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J Biol Chem 1997; 272: 26953–8.
   PubMed Web of Science ®Google Scholar
• Ahmad M, Srinivasula SM, Wang L, et al. CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer Res 1997; 57: 615–9.
   PubMed Web of Science ®Google Scholar
• Duan H, Dixit VM. RAIDD is a new ‘death’ adaptor molecule. Nature 1997; 385: 86–9.
   PubMed Web of Science ®Google Scholar
• Vincenz C, Dixit VM. Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. J Biol Chem 1997; 272: 6578–83.
   PubMed Web of Science ®Google Scholar
• Zhang J, Cado D, Chen A, et al. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 1998; 392: 296–300.
   PubMed Web of Science ®Google Scholar
• Tewari M, Quan LT, O’Rourke K, et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) poly-merase. Cell 1995; 81: 801–9.
   PubMed Web of Science ®Google Scholar
• Fernandes-Alnemri T, Litwack G Alnemri ES. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem 1994; 269: 30761–4.
   PubMed Web of Science ®Google Scholar
• Nicholson DW, Ali A, Thornberry NA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995; 376: 37–43.
   PubMed Web of Science ®Google Scholar
• Srinivasula SM, Ahmad M, Fernandes-Alnemri T, et al. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc Natl Acad Sci USA 1996; 93: 14486–91.
   PubMed Web of Science ®Google Scholar
• Fernandes-Alnemri T, Takahashi A, Armstrong R, et al. Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer Res 1995; 55: 6045–52.
   PubMed Web of Science ®Google Scholar
• Dbaibo GS, Perry DK, Gamard CJ, et al. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med 1997; 185: 481–90.
   PubMed Web of Science ®Google Scholar
• Zhou Q, Snipas S, Orth K, et al. Target protease specificity of the viral serpin CrmA. Analysis of five caspases. J Biol Chem 1997; 272: 7797–800.
   PubMedGoogle Scholar
• Li P, Allen H, Banerjee S, et al. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 1995; 80: 401–11.
   PubMed Web of Science ®Google Scholar
• Rothe M, Wong SC, Henzel WJ, et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994; 78: 681–92.
   PubMed Web of Science ®Google Scholar
• Weiss T, Grell M, Siemienski K, et al. TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J Immunol 1998; 161: 3136–42.
   PubMed Web of Science ®Google Scholar
• Rothe M, Pan MG, Henzel WJ, et al. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 1995; 83: 1243–52.
   PubMed Web of Science ®Google Scholar
• Baker SJ, Reddy EP. Modulation of life and death by the TNF receptor superfamily. Oncogene 1998; 17: 3261–70.
   PubMed Web of Science ®Google Scholar
• Arch RH, Gedrich RW Thompson CB. Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death. Gene Dev 1998; 12: 2821–30.
   Google Scholar
• Hsu H, Shu HB, Pan MG, et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996; 84: 299–308.
   PubMed Web of Science ®Google Scholar
• Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-a-induced cell death. Science 1996; 274: 782–4.
   PubMed Web of Science ®Google Scholar
• Van Antwerp DJ, Martin SJ, Kafri T, et al. Suppression of TNFa-induced apoptosis by NF-kappaB. Science 1996; 274: 787–9.
   PubMed Web of Science ®Google Scholar
• Wang CY, Mayo MW Baldwin AS Jr. TNF- and cancer therapy-induced apoptosis: potentia-tion by inhibition of NF-kappaB. Science 1996; 274: 784–7.
   Google Scholar
• Wu M, Lee H, Bellas RE, et al. Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J 1996; 15: 4682–90.
   PubMed Web of Science ®Google Scholar
• Lee SY, Reichlin A, Santana A, et al. TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. Immunity 1997; 7: 703–13.
   PubMed Web of Science ®Google Scholar
• Yeh WC, Shahinian A, Speiser D, et al. Early lethality, functional NF-kB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997; 7: 715–25.
   PubMed Web of Science ®Google Scholar
• Shu HB, Takeuchi M Goeddel DV. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci USA 1996; 93: 13973–8.
   PubMed Web of Science ®Google Scholar
• Song HY, Rothe M Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kB activation. Proc Natl Acad Sci USA 1996; 93: 6721–5.
   PubMed Web of Science ®Google Scholar
• Cheng G, Baltimore D. TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-kB activation. Gene Dev 1996; 10: 963–73.
   PubMed Web of Science ®Google Scholar
• Rothe M, Xiong J, Shu HB, et al. I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction. Proc Natl Acad Sci USA 1996; 93: 8241–6.
   PubMed Web of Science ®Google Scholar
• Liu ZG, Hsu H, Goeddel DV, et al. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death. Cell 1996; 87: 565–76.
   PubMed Web of Science ®Google Scholar
• Kelliher MA, Grimm S, Ishida Y, et al. The death domain kinase RIP mediates the TNF-induced NF-kB signal. Immunity 1998; 8: 297–303.
   PubMed Web of Science ®Google Scholar
• Natoli G, Costanzo A, Ianni A, et al. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science 1997; 275: 200–3.
   PubMed Web of Science ®Google Scholar
• Reinhard C, Shamoon B, Shyamala V, et al. Tumor necrosis factor alpha-induced activation of c-jun N-terminal kinase is mediated by TRAF2. EMBO J 1997; 16: 1080–92.
   PubMedGoogle Scholar
• Nishitoh H, Saitoh M, Mochida Y, et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell 1998; 2: 389–95.
   PubMed Web of Science ®Google Scholar
• Johnson NL, Gardner AM, Diener KM, et al. Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death. J Biol Chem 1996; 271: 3229–37.
   PubMed Web of Science ®Google Scholar
• Yang DD, Kuan CY, Whitmarsh AJ, et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 1997; 389: 865–70.
   PubMed Web of Science ®Google Scholar
• Sakata N, Patel HR, Terada N, et al. Gelfand EW. Selective activation of c-Jun kinase mitogen-activated protein kinase by CD40 on human B cells. J Biol Chem 1995; 270: 30823–8.
   PubMed Web of Science ®Google Scholar
• Westwick JK, Weitzel C, Leffert HL, et al. Activation of Jun kinase is an early event in hepatic regeneration. J Clin Invest 1995; 95: 803–10.
   Google Scholar
• Hsueh YP, Lai MZ. c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes. J Biol Chem 1995; 270: 18094–8.
   PubMedGoogle Scholar
• Goillot E, Raingeaud J, Ranger A, et al. Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci USA 1997; 94: 3302–7.
   PubMed Web of Science ®Google Scholar
• Hannun YA. The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 1994; 269: 3125–8.
   PubMed Web of Science ®Google Scholar
• Kolesnick R, Golde DW. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 1994; 77: 325–8.
   PubMed Web of Science ®Google Scholar
• Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. TIBS 1995; 20: 74–7.
   Google Scholar
• Jarvis WD, Fornari FA, Traylor RS, et al. Induction of apoptosis and potentiation of ceramide-mediated cytotoxicity by sphingoid bases in human myeloid leukemia cells. J Biol Chem 1996; 271: 8275–84.
   PubMed Web of Science ®Google Scholar
• Harada-Shiba M, Kinoshita M, Kamido H, et al. Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms. J Biol Chem 1998; 273: 9681–7.
   PubMed Web of Science ®Google Scholar
• Amarante-Mendes GP, Naekyung Kim C, Liu L, et al. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. Blood 1998; 91: 1700–5.
   PubMed Web of Science ®Google Scholar
• Yoshimura S, Banno Y, Nakashima S, et al. Ceramide formation leads to caspase-3 activation during hypoxic PC12 cell death. Inhibitory effects of Bcl-2 on ceramide formation and caspase-3 activation. J Biol Chem 1998; 273: 6921–7.
   PubMed Web of Science ®Google Scholar
• Yen CLE, Mar MH Zeisel SH. Choline deficiency-induced apoptosis in PC12 cells is associated with diminished membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide and diacylglycerol, and activation of a caspase. FASEB J 1999; 13: 135–142.
   PubMed Web of Science ®Google Scholar
• Harvey KF, Harvey NL, Michael JM, et al. Caspase-mediated cleavage of the ubiquitin-protein ligase Nedd4 during apoptosis. J Biol Chem 1998; 273: 13524–30.
   Google Scholar
• Ham J, Babij C, Whitfield J, et al. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 1995; 14: 927–39.
   PubMed Web of Science ®Google Scholar
• Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275: 90–4.
   PubMed Web of Science ®Google Scholar
• Sawai H, Okazaki T, Yamamoto H, et al. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem 1995; 270: 27326–31.
   PubMed Web of Science ®Google Scholar
• Zanke BW, Boudreau K, Rubie E, et al. The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat. Curr Biol 1996; 6: 606–13.
   PubMed Web of Science ®Google Scholar
• Santana P, Peña LA, Haimovitz-Friedman A, et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 1996; 86: 189–99.
   PubMed Web of Science ®Google Scholar
• Schwandner R, Wiegmann K, Bernardo K, et al. TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 1998; 273: 5916–22.
   PubMed Web of Science ®Google Scholar
• Chinnaiyan AM, Tepper CG, Seldin MF, et al. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 1996; 271: 4961–5.
   PubMed Web of Science ®Google Scholar
• Watts JD, Gu M, Patterson SD, et al. On the complexities of ceramide changes in cells undergoing apoptosis: lack of evidence for a second messenger function in apoptotic induction. Cell Death Differ 1999; 6: 105–114.
   PubMedGoogle Scholar
• Karasavvas N, Zakeri Z. Relationships of apoptotic signaling mediated by ceramide and TNF-a in U937 cells. Cell Death Differ 1999; 6: 115–123.
   Google Scholar
• Scurlock B, Dawson G. Differential responses of oligodendrocytes to tumor necrosis factor and other pro-apoptotic agents: Role of ceramide in apoptosis. J Neurosci Res 1999; 55: 514–522.
   PubMed Web of Science ®Google Scholar
• Smyth MJ, Perry DK, Zhang J, et al. prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2. Biochem J 1996; 316: 25–8.
   PubMed Web of Science ®Google Scholar
• Sweeney EA, Inokuchi J Igarashi Y. Inhibition of sphingolipid induced apoptosis by caspase inhibitors indicates that sphingosine acts in an earlier part of the apoptotic pathway than ceramide. FEBS Lett 1998; 425: 61–5.
   PubMedGoogle Scholar
• Genestier L, Prigent AF, Paillot R, et al. Caspase-dependent ceramide production in Fas- and HLA class I-mediated peripheral T cell apoptosis. J Biol Chem 1998; 273: 5060–6.
   Google Scholar
• Pronk GJ, Ramer K, Amiri P, et al. Requirement of an ICE-like protease for induction of apoptosis and ceramide generation by REAPER. Science 1996; 271: 808–10.
   PubMed Web of Science ®Google Scholar
• Bose R, Chen P, Loconti A, et al. Ceramide generation by the Reaper protein is not blocked by the caspase inhibitor, p35. J Biol Chem 1998; 273: 28852–9.
   Google Scholar
• Herr I, Wilhelm D, Bohler T, et al. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 1997; 16: 6200–8.
   PubMed Web of Science ®Google Scholar
• Casaccia-Bonnefil P, Carter BD, Dobrowsky RT, et al. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 1996; 383: 716–9.
   PubMed Web of Science ®Google Scholar
• Frade JM, Rodriguez-Tebar A Barde YA. Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature 1996; 383: 166–8.
   PubMed Web of Science ®Google Scholar
• Dobrowsky RT. Carter BD. Coupling of the p75 neurotrophin receptor to sphingolipid signaling. Ann NY Acad Sci 1998; 845: 32–45.
   Google Scholar
• Dobrowsky RT, Jenkins GM Hannun YA. Neurotrophins induce sphingomyelin hydrolysis. Modulation by co-expression of p75NTR with Trk receptors. J Biol Chem 1995; 270: 22135–42.
   PubMedGoogle Scholar
• Casaccia-Bonnefil P, Aibel L Chao MV. Central glial and neuronal populations display differential sensitivity to ceramide-dependent cell death. J Neurosci Res 1996; 43: 382–9.
   Google Scholar
• Brugg B, Michel PP, Agid Y, et al. Ceramide induces apoptosis in cultured mesencephalic neurons. J Neurochem 1996; 66: 733–9.
   PubMed Web of Science ®Google Scholar
• Hartfield PJ, Mayne GC Murray AW. Ceramide induces apoptosis in PC12 cells. FEBS Lett 1997; 401: 148–52.
   PubMed Web of Science ®Google Scholar
• Khursigara G, Orlinick JR Chao MV. Association of the p75 neurotrophin receptor with TRAF6. J Biol Chem 1999; 274: 2597–2600.
   PubMed Web of Science ®Google Scholar
• Laethem RM, Hannun YA, Jayadev S, et al. Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843. Blood 1998; 91: 4350–60.
   Google Scholar
• Bose R, Verheij M, Haimovitz-Friedman A, et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995; 82: 405–14.
   PubMed Web of Science ®Google Scholar
• Boland MP, Foster SJ O’Neill LA. Daunorubicin activates NFkB and induces kappaB-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells. J Biol Chem 1997; 272: 12952–60.
   PubMed Web of Science ®Google Scholar
• Jaffrezou JP, Levade T, Bettaieb A, et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 1996; 15: 2417–24.
   PubMed Web of Science ®Google Scholar
• Durrieu F, Belloc F, Lacoste L, et al. Caspase activation is an early event in anthracycline-induced apoptosis and allows detection of apoptotic cells before they are ingested by phagocytes. Exp Cell Res 1998; 240: 165–75.
   PubMed Web of Science ®Google Scholar
• Adam D, Wiegmann K, Adam-Klages S, et al. A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway. J Biol Chem 1996; 271: 14617–22.
   PubMed Web of Science ®Google Scholar
• Adam-Klages S, Adam D, Wiegmann K, et al. FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neu-tral sphingomyelinase. Cell 1996; 86: 937–47.
   PubMed Web of Science ®Google Scholar
• Tepper CG, Jayadev S, Liu B, et al. Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc Natl Acad Sci USA 1995; 92: 8443–7.
   PubMed Web of Science ®Google Scholar
• Chmura SJ, Nodzenski E, Weichselbaum RR, et al. Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase. Cancer Res 1996; 56: 2711–4.
   Google Scholar
• Gottschalk AR, Quintans J. Apoptosis in B lymphocytes: the WEHI-231 perspective. Immunol Cell Biol 1995; 73: 8–16.
   PubMed Web of Science ®Google Scholar
• Andrieu N, Salvayre R Levade T. Evidence against involvement of the acid lysosomal sphingomyelinase in the tumor necrosis factor and interleukin-1-induced sphingomyelin cycle and cell proliferation in human fibroblasts. Biochem J 1994; 303: 341–5.
   PubMed Web of Science ®Google Scholar
• Kuno K, Sukegawa K, Ishikawa Y, et al. Acid sphingomyelinase is not essential for the IL-1 and tumor necrosis factor receptor signaling pathway leading to NFkB activation. Int Immunol 1994; 6: 1269–72.
   Google Scholar
• Shirakabe K, Yamaguchi K, Shibuya H, et al. TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 1997; 272: 8141–4.
   PubMed Web of Science ®Google Scholar
• Hurwitz R, Ferlinz K Sandhoff K. The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem H-S 1994; 375: 447–50.
   PubMed Web of Science ®Google Scholar
• Slowik MR, De Luca LG, Min W, et al. Ceramide is not a signal for tumor necrosis factor-induced gene expression but does cause programmed cell death in human vascular endothelial cells. Circ Res 1996; 79: 736–47.
   Google Scholar
• Rizzo MT, Carlo-Stella C. Arachidonic acid mediates interleukin-1 and tumor necrosis factor-alpha-induced activation of the c-jun amino-terminal kinases in stromal cells. Blood 1996; 88: 3792–800.
   PubMed Web of Science ®Google Scholar
• Butterfield L, Storey B, Maas L, et al. c-Jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation. J Biol Chem 1997; 272: 101 10–6.
   Google Scholar
• Zumbansen M, Stoffel W. Tumor necrosis factor alpha activates NF-kB in acid sphingomyelinase-deficient mouse embryonic fibroblasts. J Biol Chem 1997; 272: 10904–9.
   PubMedGoogle Scholar
• Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–12.
   PubMed Web of Science ®Google Scholar
• Susin SA, Zamzami N, Larochette N, et al. A cytofluorometric assay of nuclear apoptosis induced in a cell-free system: application to ceramide-induced apoptosis. Exp Cell Res 1997; 236: 397–403.
   PubMedGoogle Scholar
• Marzo I, Brenner C, Zamzami N, et al. The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 1998; 187: 1261–71.
   PubMed Web of Science ®Google Scholar
• Susin SA, Zamzami N, Castedo M, et al. The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis. J Exp Med 1997; 186: 25–37.
   PubMed Web of Science ®Google Scholar
• Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91: 479–89.
   PubMed Web of Science ®Google Scholar
• Zou H, Henzel WJ, Liu X, et al. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90: 405–13.
   PubMed Web of Science ®Google Scholar
• Adachi S, Cross AR Babior BM. Bcl-2 and the outer mitochondrial membrane in the inacti-vation of cytochrome c during Fas-mediated apoptosis. J Biol Chem 1997; 272: 21878–82.
   PubMed Web of Science ®Google Scholar
• Hakem R, Hakem A, Duncan GS, et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998; 94: 339–52.
   PubMed Web of Science ®Google Scholar
• Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 1998; 94: 325–37.
   PubMed Web of Science ®Google Scholar
• Vander Heiden MG, Chandel NS, Williamson EK, et al. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 1997; 91: 627–37.
   PubMed Web of Science ®Google Scholar
• Rosse T, Olivier R, Monney L, et al. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 1998; 391: 496–9.
   PubMed Web of Science ®Google Scholar
• Reed JC. Bcl-2 family proteins. Oncogene 1998; 17: 3225–36.
   PubMed Web of Science ®Google Scholar
• Pan G, O’Rourke K Dixit VM. Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J Biol Chem 1998; 273: 5841–5.
   PubMed Web of Science ®Google Scholar
• Hu Y, Benedict MA, Wu D, et al. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc Natl Acad Sci USA 1998; 95: 4386–91.
   PubMed Web of Science ®Google Scholar
• Wang HG, Rapp UR Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 1996; 87: 629–38.
   PubMed Web of Science ®Google Scholar
• Zha J, Harada H, Yang E, et al. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 1996; 87: 619–28.
   PubMed Web of Science ®Google Scholar
• Kuwana T, Smith JJ, Muzio M, et al. Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem 1998; 273: 16589–94.
   PubMedGoogle Scholar
• Luo X, Budihardjo I, Zou H, et al. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94: 481–90.
   PubMed Web of Science ®Google Scholar
• Li H, Zhu H, Xu CJ, et al. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491–501.
   PubMed Web of Science ®Google Scholar
• Bossy-Wetzel E, Newmeyer DD Green DR. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998; 17: 37–49.
   PubMed Web of Science ®Google Scholar
• Garcia-Ruiz C, Colell A, Mari M, et al. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glu-tathione. J Biol Chem 1997; 272: 11369–77.
   PubMed Web of Science ®Google Scholar
• Arora AS, Jones BJ, Patel TC, et al. Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat. Hepatology 1997; 25: 958–63.
   PubMedGoogle Scholar
• Pastorino JG, Simbula G, Yamamoto K, et al.The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition. J Biol Chem 1996; 271: 29792–8.
   PubMed Web of Science ®Google Scholar
• Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132–6.
   PubMed Web of Science ®Google Scholar
• Ghafourifar P, Klein SD, Schucht O, et al. Ceramide induces cytochrome c release from isolated mitochondria — importance of mitochondrial redox state. J Biol Chem 1999; 274: 6080–6084.
   PubMed Web of Science ®Google Scholar
• Cecconi F, Alvarez-Bolado G, Meyer BI, et al. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998; 94: 727–37.
   PubMed Web of Science ®Google Scholar
• El-Assaad W, El-Sabban M, Awaraji C, et al. Distinct sites of action of Bcl-2 and Bcl-xL in the ceramide pathway of apoptosis. Biochem J 1998; 336: 735–41.
   Google Scholar
• Quillet-Mary A, Jaffrezou JP, Mansat V, et al. Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 1997; 272: 21388–95.
   PubMed Web of Science ®Google Scholar
• Liu B, Hannun YA. Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 1997; 272: 16281–7
   PubMedGoogle Scholar
• Goldkorn T, Balaban N, Matsukuma K, et al. EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am J Resp Cell Mol Biol 1998; 19: 786–98.
   PubMedGoogle Scholar
• Ghosh TK, Bian J Gill DL. Sphingosine 1-phosphate generated in the endoplasmic reticulum membrane activates release of stored calcium. J Biol Chem 1994; 269: 22628–35.
   PubMed Web of Science ®Google Scholar
• Mattie M, Brooker G Spiegel S. Sphingosine-1-phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol trisphosphate-independent pathway. J Biol Chem 1994; 269: 3181–8.
   PubMed Web of Science ®Google Scholar
• Zhang H, Desai NN, Olivera A, et al. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J Cell Biol 1991; 114: 155–67.
   PubMed Web of Science ®Google Scholar
• Sakano S, Takemura H, Yamada K, et al. Ohshika H. Ca++ mobilizing action of sphingosine in Jurkat human leukemia T cells. Evidence that sphingosine releases Ca++ from inositol trisphosphate- and phosphatidic acid-sensitive intracellular stores through a mechanism independent of inositol trisphosphate. J Biol Chem 1996; 271: 11148–55.
   Google Scholar
• Jacobs LS, Kester M. Sphingolipids as mediators of effects of platelet-derived growth factor in vascular smooth muscle cells. Am J Phys 1993; 265: C740–7.
   Google Scholar
• Wong K, Kwan-Yeung L. Sphingosine mobilizes intracellular calcium in human neutrophils. Cell Calcium 1993; 14: 493–505.
   Google Scholar
• Sitges M, Talamo BR. Sphingosine, W-7, and trifluoperazine inhibit the elevation in cytosolic calcium induced by high K+ depolarization in synaptosomes. J Neurochem 1993; 61: 443–50.
   PubMed Web of Science ®Google Scholar
• McDonough PM, Yasui K, Betto R, et al. Control of cardiac Ca++ levels. Inhibitory actions of sphingosine on Ca++ transients and L-type Ca++ channel conductance. Circ Res 1994; 75: 981–9.
   PubMed Web of Science ®Google Scholar
• van Echten-Deckert G, Schick A, Heinemann T, et al. Phosphorylated cis-4-methylsphingosine mimics the mitogenic effect of sphingosine-1-phosphate in Swiss 3T3 fibroblasts. J Biol Chem 1998; 273: 23585–9.
   Google Scholar
• Webster RJ, Sabbadini RA, Dettbarn CA, et al. Sphingosine effects on the contractile behavior of skinned cardiac myocytes. J Mol Cell Cardiol 1994; 26: 1273–90.
   Google Scholar
• Tokura Y, Wakita H, Yagi H, et al. Th2 suppressor cells are more susceptible to sphingosine than Th1 cells in murine contact photosensitivity. Source J Invest Dermatol 1996; 107: 34–40.
   Google Scholar
• Mathes C, Fleig A Penner R. Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine. J Biol Chem 1998; 273: 25020–30.
   PubMed Web of Science ®Google Scholar
• Tornquist K, Pasternack M Kaila K. Sphingosine derivatives inhibit depolarization-evoked calcium entry in rat GH4C1 cells. Endocrinology 1995; 136: 4894–902.
   Google Scholar
• Sugiya H, Furuyama S. Sphingosine stimulates calcium mobilization in rat parotid acinar cells. FEBS Lett 1991; 286: 113–6.
   Google Scholar
• Chao CP, Laulederkind SJ Ballou LR. Sphingosine-mediated phosphatidylinositol metabolism and calcium mobilization. J Biol Chem 1994; 269: 5849–56.
   Google Scholar
• Postma FR, Jalink K, Hengeveld T, et al. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J 1996; 15: 2388–92.
   PubMed Web of Science ®Google Scholar
• Yatomi Y, Ruan F, Hakomori S, et al. Sphingosine-1-phosphate: a platelet-activating sphin-golipid released from agonist-stimulated human platelets. Blood 1995; 86: 193–202.
   PubMed Web of Science ®Google Scholar
• Negishi T, Chik CL Ho AK. Ceramide selectively inhibits calcium-mediated potentiation of beta-adrenergic-stimulated cyclic nucleotide accumulation in rat pinealocytes. Biochem Biophys Res Commun 1998; 244: 57–61.
   Google Scholar
• Schreur KD, Liu S. Involvement of ceramide in inhibitory effect of IL-1 beta on L-type Ca++ current in adult rat ventricular myocytes. Am J Phys 1997; 272: H2591–8.
   Google Scholar
• Furukawa K, Mattson MP. The transcription factor NF-kB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 1998; 70: 1876–86.
   PubMed Web of Science ®Google Scholar
• Wong K, Li XB. C6-ceramide maintains elevated cytosolic calcium levels in activated platelets. Thromb Res 1996; 81: 219–29.
   Google Scholar
• Richard A, Bourgoin S, Naccache PH, et al. C2-ceramide primes specifically for the superox-ide anion production induced by N-formylmethionylleucyl phenylalanine (fMLP) in human neutrophils. Biochim Biophys Acta 1996; 1299: 259–66.
   Google Scholar
• Hannun YA, Loomis CR, Merrill AH Jr, et al. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem 1986; 261: 12604–9.
   PubMed Web of Science ®Google Scholar
• Hannun YA, Bell RM. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 1987; 235: 670–4.
   PubMed Web of Science ®Google Scholar
• Hannun YA, Bell RM. Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. Science 1989; 243: 500–7.
   PubMed Web of Science ®Google Scholar
• Merrill AH Jr, Nimkar S, Menaldino D, et al. Structural requirements for long-chain (sphingoid) base inhibition of protein kinase C in vitro and for the cellular effects of these compounds. Biochemistry 1989; 28: 3138–45.
   Google Scholar
• Coroneos E, Martinez M, McKenna S, et al. Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation. J Biol Chem 1995; 270: 23305–9.
   PubMed Web of Science ®Google Scholar
• Schroeder JJ, Crane HM, Xia J, et al. Disruption of sphingolipid metabolism and stimulation of DNA synthesis by fumonisin B1. A molecular mechanism for carcinogenesis associated with Fusarium moniliforme. J Biol Chem 1994; 269: 3475–81.
   Google Scholar
• Hauser JM, Buehrer BM Bell RM. Role of ceramide in mitogenesis induced by exogenous sphingoid bases. J Biol Chem 1994; 269: 6803–9.
   Google Scholar
• Wakita H, Tokura Y, Yagi H, et al. Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine. Arch Dermatol Res 1994; 286: 350–4.
   PubMed Web of Science ®Google Scholar
• Alesenko AV, Pantaz EA, Pushkareva MIu, et al. [Change in the level of endogenous sphingosine in cell nuclei from regenerating rat liver]. Izmenenie urovnia endogennogo sfingozina v iadrakh kletok regeneriruiushchei pecheni krys. Biokhimiia 1993; 58: 461–70.
   Google Scholar
• Ella KM, Qi C, Dolan JW, et al. Characterization of a sphingomyelinase activity in Saccha-romyces cerevisiae. Arch Biochem Biophys 1997; 340: 101–10.
   Google Scholar
• Yamada T, Okajima F, Ohwada S, et al. Growth inhibition of human pancreatic cancer cells by sphingosylphosphorylcholine and influence of culture conditions. Cell Mol Life Sci 1997; 53: 435–41.
   Google Scholar
• Hashizume T, Nakao M Sato T. Sphingosine enhances phosphatidylinositol 4-kinase activity in rabbit platelets. J Biochem 1996; 120: 61–5.
   Google Scholar
• Ohta H, Yatomi Y, Sweeney EA, et al. A possible role of sphingosine in induction of apoptosis by tumor necrosis factor-alpha in human neutrophils. FEBS Lett 1994; 355: 267–70.
   PubMedGoogle Scholar
• Krown KA, Page MT, Nguyen C, et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996; 98: 2854–65.
   PubMed Web of Science ®Google Scholar
• Alesenko AV, Boikov PIa, Drobot LB, et al. Filippova GN. [Change in the level of sphin-gosine in rat liver nuclei and cells during oncogene superexpression induced by cyclohexim-ide]. Izmenenie urovnia sfingozina v iadrakh i kletkakh pecheni krys pri indutsirovannoi superekspressii onkogenov tsiklogeksimidom. Biokhimiia 1994; 59: 1076–87.
   Google Scholar
• Olivera A, Zhang H, Carlson RO, et al. Spiegel S. Stereospecificity of sphingosine-induced intracellular calcium mobilization and cellular proliferation. J Biol Chem 1994; 269: 17924–30.
   Google Scholar
• Megidish T, White T, Takio K, et al. The signal modulator protein 14-3-3 is a target of sphingosine-or N,N-dimethylsphingosine-dependent kinase in 3T3(A31) cells. Biochem Biophys Res Commun 1995; 216: 739–47.
   PubMedGoogle Scholar
• Megidish T, Cooper J, Zhang L, et al. A novel sphingosine-dependent protein kinase (SDK1) specifically phosphorylates certain isoforms of 14-3-3 protein. J Biol Chem 1998; 273: 21834–45.
   PubMed Web of Science ®Google Scholar
• Wang F, Buckley NE, Olivera A, et al. Involvement of sphingolipids metabolites in cellular proliferation modulated by ganglioside GM1. Glycoconjugate J 1996; 13: 937–45.
   PubMed Web of Science ®Google Scholar
• Kohama T, Olivera A, Edsall L, et al. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 1998; 273: 23722–8.
   PubMed Web of Science ®Google Scholar
• Cuvillier O, Rosenthal DS, Smulson ME, et al. 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. J Biol Chem 1998; 273: 2910–6.
   PubMed Web of Science ®Google Scholar
• Kleuser B, Cuvillier O Spiegel S. 1Alpha,25-dihydroxyvitamin D3 inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res 1998; 58: 1817–24.
   PubMed Web of Science ®Google Scholar
• Ohta H, Sweeney EA, Masamune A, et al. Induction of apoptosis by sphingosine in human leukemic HL-60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester-induced differentiation. Cancer Res 1995; 55: 691–7.
   PubMed Web of Science ®Google Scholar
• Kishida E, Yano M, Kasahara M, et al. Distinctive inhibitory activity of docosahexaenoic acid against sphingosine-induced apoptosis. Biochim Biophys Acta 1998; 1391: 401–8.
   PubMed Web of Science ®Google Scholar
• Spiegel S, Cuvillier O, Edsall LC, et al. Sphingosine-1-phosphate in cell growth and cell death. Ann NY Acad Sci 1998; 845: 11–8.
   PubMed Web of Science ®Google Scholar
• Edsall LC, Van Brocklyn JR, Cuvillier O, et al. N,N-Dimethylsphingosine is a potent competitive inhibitor of sphingosine kinase but not of protein kinase C: modulation of cellular levels of sphingosine 1-phosphate and ceramide. Biochemistry 1998; 37: 12892–8.
   PubMed Web of Science ®Google Scholar
• Mandala SM, Thornton R, Tu Z, et al. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc Natl Acad Sci USA 1998; 95: 150–5.
   PubMed Web of Science ®Google Scholar
• Yatomi Y, Yamamura S, Ruan F, et al. Sphingosine 1-phosphate induces platelet activation through an extracellular action and shares a platelet surface receptor with lysophosphatidic acid. J Biol Chem 1997; 272: 5291–7.
   PubMed Web of Science ®Google Scholar
• Yamamura S, Yatomi Y, Ruan F, et al. Sphingosine 1-phosphate regulates melanoma cell motility through a receptor-coupled extracellular action and in a pertussis toxin-insensitive manner. Biochemistry 1997; 36: 107519.
   Google Scholar
• van Koppen C, Meyer zu Heringdorf M, Laser KT, et al. Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate. J Biol Chem 1996; 271: 2082–7.
   PubMed Web of Science ®Google Scholar
• Igarashi Y. Sphingosine-1-phosphate as an intercellular signaling molecule. Ann NY Acad Sci 1998; 845: 19–31.
   PubMedGoogle Scholar
• Lee MJ, Van Brocklyn JR, Thangada S, et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 1998; 279: 1552–5.
   PubMed Web of Science ®Google Scholar
• Gomez-Munoz A. Modulation of cell signalling by ceramides. Biochim Biophys Acta 1998; 1391: 92–109.
   Google Scholar
• Gomez-Munoz A, Frago LM, Alvarez L, et al. Stimulation of DNA synthesis by natural ceramide 1-phosphate. Biochem J 1997; 325: 435–40.
   Google Scholar
• Bettaieb A, Plo I, Mansat-De Mas V, et al. Daunorubicin- and mitoxantrone-triggered phos-phatidylcholine hydrolysis: Implication in drug-induced ceramide generation and apoptosis. Mol Pharmacol 1999; 55: 118–125.
   PubMed Web of Science ®Google Scholar
• Laurenz JC, Gunn JM, Jolly CA, et al. Alteration of glycerolipid and sphingolipid-derived second messenger kinetics in ras transformed 3T3 cells. Biochim Biophys Acta 1996; 1299: 146–54.
   Google Scholar
• Huang HW, Goldberg EM Zidovetzki R. Ceramides perturb the structure of phosphatidylcho-line bilayers and modulate the activity of phospholipase A2. Eur Biophys J 1998; 27: 361–6.
   Google Scholar
• Wang YM, Seibenhener ML, Vandenplas ML, et al. Atypical PKCz is activated by ceramide, resulting in coactivation of NF-kB/JNK kinase and cell survival J Neurosci Res 1999; 55: 293–302.
   PubMed Web of Science ®Google Scholar