Cell Biochemistry and Biophysics

, Volume 40, Issue 3, pp 323–350 | Cite as

Ceramide and other sphingolipids in cellular responses

  • Jun Yang
  • Yingnian Yu
  • Shuyu Sun
  • Penelope J. Duerksen-Hughes
Review Article


Formerly considered to serve only as structural components, sphingolipids are emerging as an important group of signaling molecules involved in many cellular events, including cell growth, senescence, meiotic maturation, and cell death. They are also implicated in functions such as inflammation and the responses to heat shock and genotoxic stress. Defects in the metabolism of sphingolipids are related to various genetic disorders, and sphingolipids have the potential to serve as therapeutic agents for human diseases such as colon cancer and viral or bacterial infections. The best-studied member of this family, ceramide, which also serves as the structural back-bone for other sphingolipids, is an important mediator in multiple cellular signaling pathways. The metabolism and functions of sphingolipids are discussed in this review, with a focus on ceramide regulation in various cellular responses.

Index Entries

Sphingolipids ceramide stress response growth control apoptosis 


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  1. 1.
    Horejsi, V., Drbal, K., Cebecauer, M., Cerny, J., Brdicka, T., Angelisova, P., et al. (1999) GPI-microdomains: a role in signalling via immunoreceptors. Immunol. Today 20, 356–361.PubMedGoogle Scholar
  2. 2.
    Cremesti, A. E., Goni, F. M., and Kolesnick, R. (2002) Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome?. FEBS Lett. 531, 47–53.PubMedGoogle Scholar
  3. 3.
    Hannun, Y. A. Sphingolipid-Mediated Signal Transduction. R. G. Landes Company, Austin, TX, 1997.Google Scholar
  4. 4.
    Merrill, A. H., Jr., Schmelz, E.-M., Dillehay, D. L., Spiegel, S., Shayman, J. A., Schroeder, J. J. et al. (1997) Sphingolipids—the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol. Applied Pharmacol. 142, 208–225.Google Scholar
  5. 5.
    Prieschl, E. E. and Baumruker, T. (2000) Sphingolipids: second messengers, mediators and raft constituents in signaling. Immunol. Today 21, 555–560.PubMedGoogle Scholar
  6. 6.
    Ohanian, J. and Ohanian, V. (2001) Sphingolipids in mammalian cell signalling. Cell Mol. Life Sci. 58, 2053–2068.PubMedGoogle Scholar
  7. 7.
    Jarvis, W. D. and Grant, S. (1998) The role of ceramide in the cellular response to cytotoxic agents. Curr. Opin. Oncol. 10, 552–559.PubMedGoogle Scholar
  8. 8.
    Dbaibo, G. S. (1997) Regulation of the stress response by ceramide. Biochem. Soc. Trans. 25, 557–561.PubMedGoogle Scholar
  9. 9.
    Yang, J. and Duerksen-Hughes, P. J. (2001) Activation of a p53-independent, sphingolipid-mediated cytolytic pathway in p53-negative mouse fibroblast cells treated with N-methyl-N-nitro-N-nitrosoguanidine. J. Biol. Chem. 276, 27129–27135.PubMedGoogle Scholar
  10. 10.
    Luberto, C., Hassler, D. F., Signorelli, P., Okamoto, Y., Sawai, H., Boros, E., et al. (2002) Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J. Biol. Chem. 277, 41128–41139.PubMedGoogle Scholar
  11. 11.
    Colell, A., Morales, A., Fernandez-Checa, J. C., and Garcia-Ruiz, C. (2002) Ceramide generated by acidic sphingomyelinase contributes to tumor necrosis factor-alpha-mediated apoptosis in human colon HT-29 cells through glycosphingolipids formation. Possible role of ganglioside GD3. FEBS Lett. 526, 135–141.PubMedGoogle Scholar
  12. 12.
    Pru, J. K., Hendry, I. R., Davis, J. S., and Rueda, B. R. (2002) Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38(MAPK). Endocrinology 143, 4350–4357.PubMedGoogle Scholar
  13. 13.
    Geilen, C. C., Barz, S., and Bektas, M. (2001) Sphingolipid signaling in epidermal homeostasis. Current knowledge and new therapeutic approaches in dermatology. Skin Pharmacol. Appl. Skin Physiol. 14, 261–271.PubMedGoogle Scholar
  14. 14.
    Olivera, A. and Spiegel, S. (1993) Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365, 557–560.PubMedGoogle Scholar
  15. 15.
    Olivera, A., Zhang, H., Carlson, R.O., Mattie, M.E., Schmidt, R.R. and Spiegel, S. (1994) Stereospecificity of sphingosine-induced intra-cellular calcium mobilization and cellular proliferation. J. Biol. Chem. 269, 17924–17930.PubMedGoogle Scholar
  16. 16.
    Davaille, J., Li, L., Mallat, A., and Lotersztajn, S. (2002) Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. J. Biol. Chem. 277, 37323–37330.PubMedGoogle Scholar
  17. 17.
    Radin, N. S. (2002) The development of aggressive cancer: a possible role for sphingolipids. Cancer Invest. 20, 779–786.PubMedGoogle Scholar
  18. 18.
    Senchenkov, A., Litvak, D. A., and Cabot, M. C. (2001) Targeting ceramide metabolism—a strategy for overcoming drug resistance. J. Natl. Cancer Inst. 93, 347–357.PubMedGoogle Scholar
  19. 19.
    Sietsma, H., Veldman, R.J., and Kok, J. W. (2001) The involvement of sphingolipids in multidrug resistance. J. Membr. Biol. 181, 153–162.PubMedGoogle Scholar
  20. 20.
    Auge, N., Negre-Salvayre, A., Salvayre, R., and Levade, T. (2000) Sphingomyelin metabolites in vascular cell signaling and atherogenesis. Prog. Lipid. Res. 39, 207–229.PubMedGoogle Scholar
  21. 21.
    Cutler, R. G. and Mattson, M. P. (2001) Sphingomyelin and ceramide as regulators of development and lifespan. Mech. Ageing Dev. 122, 895–908.PubMedGoogle Scholar
  22. 22.
    Wyrick, P. B. (2000) Intracellular survival by Chlamydia. Cell. Microbiol. 2, 275–282.PubMedGoogle Scholar
  23. 23.
    Raulin, J. (2002) Human immunodeficiency virus and host cell lipids. Interesting pathways in research for a new HIV therapy. Prog. Lipid. Res. 41, 27–65.PubMedGoogle Scholar
  24. 24.
    van Ooij, C., Kalman, L., van Ijzendoorn, S., Nishijima, M., Hanada, K., Mostov, K., et al. (2000) Host cell-derived sphingolipids are required for the intracellular growth of Chlamydi trachomatis. Cell. Microbiol. 2, 627–637.PubMedGoogle Scholar
  25. 25.
    Schmelz, E. M., Bushnev, A. S., Dillehay, D. L., Liotta, D. C., and Merrill, A. H., Jr. (1997) Suppression of aberrant colonic crypt foci by synthetic sphingomyelins with saturated or unsaturated sphingoid base backbones. Nutr. Cancer 28, 81–85.PubMedGoogle Scholar
  26. 26.
    Schmelz, E. M. and Merrill, A. H., Jr. (1998) Ceramides and ceramide metabolites in cell regulation: evidence for dietary sphingolipids as inhibitors of colon carcinogenesis. Nutrition 14, 717–719.PubMedGoogle Scholar
  27. 27.
    Schmelz, E. M., Sullards, M. C., Dillehay, D. L., and Merrill, A. H., Jr. (2000) Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice. J. Nutr. 130, 522–527.PubMedGoogle Scholar
  28. 28.
    Berra, B., Colombo, I., Sottocornola, E., and Giacosa, A. (2002) Dietary sphingolipids in colorectal cancer prevention. Eur. J. Cancer Prev. 11, 193–197.PubMedGoogle Scholar
  29. 29.
    Hannun, Y. A., Luberto, C., and Argraves, K. M. (2001) Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry 40, 4893–4903.PubMedGoogle Scholar
  30. 30.
    Ferlinz, K., Hurwitz, R., Vielhaber, G., Suzuki, K., and Sandhoff, K. (1994) Occurrence of two molecular forms of human acid sphingomyelianse. Biochem. J. 310, 855–862.Google Scholar
  31. 31.
    Ichikawa, S., Sakiyama, H., Suzuki, G., Hidari, K. I., and Hirabayashi, Y. (1996) Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc. Natl. Acad. Sci. USA 93, 4638–4643.PubMedGoogle Scholar
  32. 32.
    Bernardo, K., Hurwitz, R., Zenk, T., Desnick, R. J., Ferlinz, K., Schuchman, E. H., and Sandhoff, K. (1995) Purification, characterization, and biosynthesis of human acid ceramidase. J. Biol. Chem. 270, 11098–11102.PubMedGoogle Scholar
  33. 33.
    Yada, Y., Higuchi, K., and Imokawa, G. (1995) Purification and biochemical characterization of membrane-bound epidermal ceramidases from guinea pig skin. J. Biol. Chem. 270, 12677–12684.PubMedGoogle Scholar
  34. 34.
    Nikolova-Karakashian, M. and Merrill, A. H. Jr. (2000) Ceramidases. Methods Enzymol. 311, 194–201.PubMedGoogle Scholar
  35. 35.
    Hanada, K., Hara, T., and Nishijima, M. (2000) Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques. J. Biol. Chem. 275, 8409–8415.PubMedGoogle Scholar
  36. 36.
    Ternes, P., Franke, S., Zahringer, U., Sperling, P., and Heinz, E. (2002) Identification and characterization of a sphingolipid delta 4-desaturase family. J. Biol. Chem. 277, 25512–25518.PubMedGoogle Scholar
  37. 37.
    Liu, H., Chakravarty, D., Maceyka, M., Milstien, S., and Spiegel, S. (2002) Sphingosine kinases: a novel family of lipid kinases. Prog. Nucleic Acid Res. Mol. Biol. 71, 493–511.PubMedGoogle Scholar
  38. 38.
    van Helvoort, A., van't Hof, W., Ritsema, T., Sandra, A., and van Meer, G. (1994) Conversion of diacylglycerol to phosphatidylcholine on the basolateral surface of epithelial (Madin-Darby canine kidney) cells. Evidence for the reverse action of a sphingomyelin synthase. J. Biol. Chem. 269, 1763–1769.PubMedGoogle Scholar
  39. 39.
    Ruvolo, P. P. (2001) Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15, 1153–1160.PubMedGoogle Scholar
  40. 40.
    Lester, R. L., Wells, G. B., Oxford, G., and Dickson, R. C. (1993) Mutant strains of Saccharomyces cerevisiae lacking sphingolipids synthesize novel inositol glycerophospholipids that mimic sphingolipid structures. J. Biol. Chem. 268, 845–856.PubMedGoogle Scholar
  41. 41.
    Hanada, K., Nishijima, M., Kiso, M., Hasegawa, A., Fujita, S., Ogawa, T., et al. (1992) Sphingolipids are essential for the growth of Chinese hamster ovary cells. Restoration of the growth of a mutant defective in sphingoid base biosynthesis by exogenous sphingolipids. J. Biol. Chem. 267, 23527–23533.PubMedGoogle Scholar
  42. 42.
    Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., and Nicholson, G. A. (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type 1. Nat. Genetics 27, 309–312.Google Scholar
  43. 43.
    Bejaoui, K., Wu, C., Scheffler, M. D., Haan, G., Ashby, P., Wu, L., et al. (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat. Genetics, 27, 261–262.Google Scholar
  44. 44.
    Dawkins, J., Brahmbhatt, S., Auer-Grumbach, M., Wagner, K., Hartung, H., Verhoeven, K., et al. (2002) Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscul. Disord. 12, 656.PubMedGoogle Scholar
  45. 45.
    Jin, H. K., Carter, J. E., Huntley, G. W., and Schuchman, E. H. (2002) Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span. J. Clin. Invest. 109, 1183–1191.PubMedGoogle Scholar
  46. 46.
    Rethy, L. A., Kalmanchey, R., Klujber, V., Koos, R., and Fekete, G. (2000) Acid sphingomyelinase deficiency in Beckwith Wiedemann syndrome. Pathol. Oncol. Res. 6, 295–297.PubMedCrossRefGoogle Scholar
  47. 47.
    Merrill, A. H., Jr. and Sweeley, C. C. Sphingolipid metabolism and cell signaling. In: Biochemistry of Lipids, Lipoproteins, and Membranes. (Vance, D. E., and Vance, J., eds.) Elsevier Science, Amsterdam, 1996, pp. 309–338.Google Scholar
  48. 48.
    Spiegel, S., Cuvillier, O., Edsall, L. C., Kohama, T., Menzeleev, R., Olah, Z., et al. (1998) Sphingosine-1-phosphate in cell growth and cell death. Ann. NY Acad. Sci., 845, 11–18.PubMedGoogle Scholar
  49. 49.
    Spiegel, S., Cuvillier, O., Edsall, L., Kohama, T., Menzeleev, R., Olivera, A., et al. (1998) Roles of sphingosine-1-phosphate in cell growth, differentiation, and death. Biochemistry (Mosc) 63, 69–73.Google Scholar
  50. 50.
    Pyne, S., Chapman, J., Steele, L., and Pyne, N. J. (1996) 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. 237, 819–826.PubMedGoogle Scholar
  51. 51.
    Zhang, H., Desai, N. N., Olivera, A., Seki, T., Brooker, G., and Spiegel, S. (1991) Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J. Cell Biol. 114, 155–167.PubMedGoogle Scholar
  52. 52.
    Gomez-Munoz, A., Waggoner, D. W., O'Brien, L., and Brindley, D. N. (1995) Interaction of ceramides, sphingosine, and sphingosine-1-phosphate in regulating DNA synthesis and phospholipase D activity. J. Biol. Chem. 270, 26318–26325.PubMedGoogle Scholar
  53. 53.
    Bornfeldt, K. E., Graves, L. M., Raines, E. W., Igarashi, Y., Wayman, G., Yamamura, S., et al. (1995) Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction. J. Cell Biol. 130, 193–206.PubMedGoogle Scholar
  54. 54.
    An, S., Zheng, Y., and Bleu, T. (2000) Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G proteincoupled receptors Edg3 and Edg5. J. Biol. Chem. 275, 288–296.PubMedGoogle Scholar
  55. 55.
    Pyne, S. and Pyne, N. J. (2002) Sphingosine 1-phosphate signalling and termination at lipid phosphate receptors. Biochim. Biophys. Acta 1582, 121–131.PubMedGoogle Scholar
  56. 56.
    Peyssonnaux, C. and Eychene, A. (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol. Cell 93, 53–62.PubMedGoogle Scholar
  57. 57.
    Yang, J., Yu, Y. N., and Duerksen-Hughes, P. J. (2003) Protein kinases and their involvement in the cellular responses to genotoxic stress. Rev. Mutat. Res. 543, 31–58.Google Scholar
  58. 58.
    Van Brocklyn, J. R., Lee, M. J., Menzeleev, R., Olivera, A., Edsall, L., Cuvillier, O., et al. (1998) Dual actions of sphingosine-1-phosphate: extracellular through the Gicoupled receptor Edg-1 and intracellular to regulate proliferation and survival. J. Cell. Biol. 142, 229–240.PubMedGoogle Scholar
  59. 59.
    Hanafusa, N., Yatomi, Y., Yamada, K., Hori, Y., Nangaku, M., Okuda, T., et al. (2002) Sphingosine 1-phosphate stimulates rat mesangial cell proliferation from outside the cells. Nephrol. Dial. Transplant 17, 580–586.PubMedGoogle Scholar
  60. 60.
    Olivera, A., Kohama, T., Edsall, L., Nava, V., Cuvillier, O., Poulton, S. et al. (1999) Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J. Cell. Biol. 147, 545–558.PubMedGoogle Scholar
  61. 61.
    Sawai, H., Okazaki, T., and Domae, N. (2002) Sphingosine-induced c-jun expression: differences between sphingosine- and C2-ceramide-mediated signaling pathways. FEBS Lett. 524, 103–106.PubMedGoogle Scholar
  62. 62.
    Ahn, E. H. and Schroeder, J. J. (2002) Sphingoid bases and ceramide induce apoptosis in HT-29 and HCT-116 human colon cancer cells. Exp. Biol. Med. 227, 345–353.Google Scholar
  63. 63.
    Chang, H. C., Tsai, L. H., Chuang, L. Y., and Hung, W. C. (2001) Role of AKT kinase in sphingosine-induced apoptosis in human hepatoma cells. J. Cell. Physiol. 188, 188–193.PubMedGoogle Scholar
  64. 64.
    Itakura, A., Tanaka, A., Aioi, A., Tonogaito, H., and Matsuda, H. (2002) Ceramide and sphingosine rapidly induce apoptosis of murine mast cells supported by interleukin-3 and stem cell factor. Exp. Hematol. 30, 272–278.PubMedGoogle Scholar
  65. 65.
    Kagedal, K., Zhao, M., Svensson, I., and Brunk, U. T. (2001) Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J. 359, 335–343.PubMedGoogle Scholar
  66. 66.
    Nava, V. E., Cuvillier, O., Edsall, L. C., Kimura, K., Milstien, S., Gelmann, E. P., et al. (2000) Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res. 60, 4468–4474.PubMedGoogle Scholar
  67. 67.
    Cuvillier, O., Edsall, L., and Spiegel, S. (2000) Involvement of sphingosine in mitochondria-dependent Fas-induced apoptosis of type II Jurkat T cells. J. Biol. Chem. 275, 15691–15700.PubMedGoogle Scholar
  68. 68.
    Matsubara, S. and Ozawa, M. (2001) Expression of alpha-catenin in alphacatenin-deficient cells increases resistance to sphingosine-induced apoptosis. J. Cell Biol. 154, 573–584.PubMedGoogle Scholar
  69. 69.
    Hung, W. C., Chang, H. C., and Chuang, L. Y. (1999) Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells. Biochem. J. 338, 161–166.PubMedGoogle Scholar
  70. 70.
    Voss, K. A., Howard, P. C., Riley, R. T., Sharma, R. P., Bucci, T. J. and Lorentzen, R. J. (2002) Carcinogenicity and mechanism of action of fumonisin B1: a mycotoxin produced by Fusarium moniliforme (=F. verticillioides). Cancer Detect. Prev. 26, 1–9.PubMedGoogle Scholar
  71. 71.
    Schmelz, E. M., Dombrink-Kurtzman, M. A., Roberts, P. C., Kozoutsumi, Y., Kawasaki, T., and Merrill, A. H., Jr. (1998) Induction of apoptosis by Fumonisin B1 in HT29 cells is mediated by the accumulation of endogenous free sphingoid bases. Toxicol. Appl. Pharmacol. 148, 252–260.PubMedGoogle Scholar
  72. 72.
    Ciacci-Zanella, J. R., Merrill, A. H., Jr., Wang, E., and Jones, C. (1998) Characterization of cell-cycle arrest by Fumonisin B1 in CV-1 cells. Food Chem. Toxicol. 36, 791–804.PubMedGoogle Scholar
  73. 73.
    Yu, C. H., Lee, Y. M., Yun, Y. P., and Yoo, H. S. (2001) Differential effects of fumonisin B1 on cell death in cultured cells: the significance of the elevated sphinganine. Arch. Pharm. Res. 24, 136–143.PubMedGoogle Scholar
  74. 74.
    Kim, M. S., Lee, Y. M., Wang, T., and Schroeder, J. J. (2001) Fumonisin B(1) induces apoptosis in LLC-PK(1) renal epithelial cells via a sphinganine-and calmodulin-dependent pathway. Toxicol. Appl. Pharmacol. 176, 118–126.PubMedGoogle Scholar
  75. 75.
    Delongchamp, R. R. and Young, J. F. (2001) Tissue sphinganine as a biomarker of fumonisin-induced apoptosis. Food Addit. Contam. 18, 255–261.PubMedGoogle Scholar
  76. 76.
    Wispriyono, B., Schmelz, E., Pelayo, H., Hanada, K., and Separovic, D. (2002) A role for the de novo sphingolipids in apoptosis of photosensitized cells. Exp. Cell Res. 279, 153–165.PubMedGoogle Scholar
  77. 77.
    Dbaibo, G. S., Pushkareva, M. Y., Jayadev, S., Schwarz, J. K., Horowitz, J. M., Obeid, L. M., and Hannun, Y. A. (1995) Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Pro. Natl. Acad. Sci. USA 92, 1347–1351.Google Scholar
  78. 78.
    Jayadev, S., Liu, B., Bielawska, A. E., Lee, J. Y., Nazaire, F., Pushkareva, M. Y., et al. (1995) Role for ceramide in cell cycle arrest. J. Biol. Chem. 270, 2047–2052.PubMedGoogle Scholar
  79. 79.
    Jarvis, W. D., Kolesnick, R. N., Fornari, F. A., Traylon, R. S., Gewirtz, D. A., and Grant, S. (1994) Induction of apototic DNA damage and cell death by activation of the sphingomyelin pathway. Proc. Natl. Acad. Sci. USA 91, 73–77.PubMedGoogle Scholar
  80. 80.
    Martin, S. J., Newmeyer, D. D., Mathias, S., Farschon, D. M., Wang, H., Reed, J. C., et al. (1995) Cell-free reconstitution of Fas-, UN radiation-and ceramide-induced apotposis. EMBO J. 14, 5191–5200.PubMedGoogle Scholar
  81. 81.
    Obeid, L. M., Linardic, C. M., Karolak, L. A., and Hannun, Y. A. (1993) Programmed cell death induced by ceramide. Science 259, 1769–1771.PubMedGoogle Scholar
  82. 82.
    Vento, R., Giuliano, M., Lauricella, M., Carabillo, M., Di Liberto, D., and Tesoriere, G. (1998) Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide. Mol. Cell. Biochem. 185, 7–15.PubMedGoogle Scholar
  83. 83.
    Pruschy, M., Resch, H., Shi, Y. Q., Aalame, N., Glanzmann, C., and Bodis, S. (1999) Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells. Br. J. Cancer 80, 693–698.PubMedGoogle Scholar
  84. 84.
    Craighead, M., Pole, J., and Waters, C. (2000) Caspases mediate C2-ceramideinduced apoptosis of the human oligodendroglial cell line, MO3.13. Neurosci. Lett. 278, 125–128.PubMedGoogle Scholar
  85. 85.
    Connor, C. E., Burrows, J., Hearps, A. C., Woods, G. M., Lowenthal, R. M., and Ragg, S. J. (2001) Cell cycle arrest of hematopoietic cell lines after treatment with ceramide is commonly associated with retinoblastoma activation. Cytometry 43, 164–169.PubMedGoogle Scholar
  86. 86.
    Poppe, M., Reimertz, C., Munstermann, G., Kogel, D., and Prehn, J. H. (2002) Ceramide-induced apoptosis of D283 medulloblastoma cells requires mitochondrial respiratory chain activity but occurs independently of caspases and is not sensitive to Bcl-xL overexpression. J. Neurochem. 82, 482–494.PubMedGoogle Scholar
  87. 87.
    Magnoni, C., Euclidi, E., Benassi, L., Bertazzoni, G., Cossarizza, A., Seidenari, S. et al. (2002) Ultraviolet B radiation induces activation of neutral and acidic sphingomyelinases and ceramide generation in cultured normal human keratinocytes. Toxicol. in Vitro 16, 349–355.PubMedGoogle Scholar
  88. 88.
    Dallalio, G., North, M., Worden, B. D., and Means, R. T., Jr. (1999) Inhibition of human erythroid colony formation by ceramide. Exp. Hematol. 27, 1133–1138.PubMedGoogle Scholar
  89. 89.
    Birbes, H., Bawab, S. E., Obeid, L. M., and Hannun, Y. A. (2002) Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv. Enzyme Regul. 42, 113–129.PubMedGoogle Scholar
  90. 90.
    Mimeault, M. (2002) New advances on structural and biological functions of ceramide in apoptotic/necrotic cell death and cancer. FEBS Lett 530, 9–16.PubMedGoogle Scholar
  91. 91.
    Kim, S. S., Chae, H. S., Bach, J. H., Lee, M. W., Kim, K. Y., Lee, W. B., et al. (2002) T53 mediates ceramide-induced apoptosis in SKN-SH cells. Oncogene 21, 2020–2028.PubMedGoogle Scholar
  92. 92.
    Tomassini, B. and Testi, R. (2002) Mitochondria as sensors of sphingolipids. Biochimie 84, 123–129.PubMedGoogle Scholar
  93. 93.
    Hearps, A. C., Burrows, J., Connor, C. E., Woods, G. M., Lowenthal, R. M., and Ragg, S. J. (2002) Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis 7, 387–394.PubMedGoogle Scholar
  94. 94.
    Jones, B. E., Lo, C. R., Srinivasan, A., Valentino, K. L., and Czaja, M. J. (1999) Ceramide induces caspase-independent apoptosis in rat hepatocytes sensitized by inhibition of RNA synthesis. Hepatology 30, 215–222.PubMedGoogle Scholar
  95. 95.
    von Haefen, C., Wieder, T., Gillissen, B., Starck, L., Graupner, V., Dorken, B., et al. (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21, 4009–4019.Google Scholar
  96. 96.
    Lee, J. Y., Leonhardt, L. G., and Obeid, L. M. (1998) Cell-cycle-dependent changes in ceramide levels preceding retinoblastoma protein dephosphorylation in G2/M. Biochem. J. 334, 457–461.PubMedGoogle Scholar
  97. 97.
    Shi, Y. Q., Wuergler, F. E., Blattmann, H., and Crompton, N. E. (2001) Distinct apoptotic phenotypes induced by radiation and ceramide in both p53-wild-type and p53-mutated lymphoblastoid cells. Radiat. Environ. Biophys. 40, 301–308.PubMedGoogle Scholar
  98. 98.
    Willaime, S., Vanhoutte, P., Caboche, J., Lemaigre-Dubreuil, Y., Mariani, J., and Brugg, B. (2001) Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation. Eur. J. Neurosci. 13, 2037–2046.PubMedGoogle Scholar
  99. 99.
    Brenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F., and Gulbins, E. (1997) Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J. Biol. Chem. 272, 22173–22181.PubMedGoogle Scholar
  100. 100.
    Jarvis, W. D., Fornari, F. A., Jr., Auer, K. L., Freemerman, A. J., Szabo, E., Birrer, M. J., et al. (1997) Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine. Mol. Pharmacol. 52, 935–947.PubMedGoogle Scholar
  101. 101.
    Buisson-Legendre, N., Bernard, P., Bobichon, H., Emonard, H., Schneider, C., Maquart, F. X., et al. (1999) Involvement of the 92-kDa gelatinase (matrix, metalloproteinase-9) in the ceramide-mediated inhibition of human keratinocyte growth. Biochem. Biophys. Res. Commun. 260, 634–640.PubMedGoogle Scholar
  102. 102.
    Pettus, B. J., Chalfant, C. E., and Hannun, Y. A. (2002) Ceramide in apoptosis: an overview and current perspectives. Biochim. Biophys. Acta 1585, 114–125.PubMedGoogle Scholar
  103. 103.
    Mathias, S., Dressler, K. A., and Kolesnick, R. N. (1991) Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. Proc. Natl. Acad. Sci. USA 88, 10009–10013.PubMedGoogle Scholar
  104. 104.
    Yao, B., Zhang, Y., Delikat, S., Mathias, S., Basu, S., and Kolesnick, R. (1995) Phosphorylation of Raf by ceramide-activated protein kinase. Nature 378, 307–310.PubMedGoogle Scholar
  105. 105.
    Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., et al. (1997) Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89, 63–72.PubMedGoogle Scholar
  106. 106.
    Basu, S., Bayoumy, S., Zhang, Y., Lozano, J., and Kolesnick, R. (1998) BAD enables ceramide to signal apoptosis via Ras and Raf-1. J. Biol. Chem. 273, 30419–30426.PubMedGoogle Scholar
  107. 107.
    Huwiler, A., Brunner, J., Hummel, R., Vervoordeldonk, M., Stabel, S., van den Bosch, H., et al. (1996) Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc. Natl. Acad. Sci. USA 93, 6959–6963.PubMedGoogle Scholar
  108. 108.
    Muller, G., Storz, P., Bourteele, S., Doppler, H., Pfizenmaier, K., Mischak, H., et al. (1998) Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling. EMBO J. 17, 732–742.PubMedGoogle Scholar
  109. 109.
    Muller, G., Ayoub, M., Storz, P., Rennecke, J., Fabbro, D., and Pfizenmaier, K. (1995) PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. EMBO J. 14, 1961–1969.PubMedGoogle Scholar
  110. 110.
    Berra, E., Diaz-Meco, M. T., Lozano, J., Frutos, S., Municio, M. M., Sanchez, P., et al. (1995) Evidence for a role of MEK and MAPK during signal transduction by protein kinase C zeta. EMBO J. 14, 6157–6163.PubMedGoogle Scholar
  111. 111.
    Diaz-Meco, M. T., Lozano, J., Municio, M. M., Berra, E., Frutos, S., Sanz, L., et al. (1994) Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta. J. Biol. Chem. 269, 31706–31710.PubMedGoogle Scholar
  112. 112.
    Wickel, M., Heinrich, M., Weber, T., Brunner, J., Kronke, M., and Schutze, S. (1999) Identification of intracellular ceramide target proteins by affinity chromatography and TID-ceramide photoaffinity labelling. Biochem. Soc. Trans. 27, 393–399.PubMedGoogle Scholar
  113. 113.
    Heinrich, M., Wickel, M., Winoto-Morbach, S., Schneider-Brachert, W., Weber, T., Brunner, J., et al. (2000) Ceramide as an activator lipid of cathepsin D. Adv. Exp. Med. Biol. 477, 305–315.PubMedGoogle Scholar
  114. 114.
    Heinrich, M., Wickel, M., Schneider-Brachert, W., Sandberg, C., Gahr, J., Schwandner, R., et al. (1999) Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 18, 5252–5263.PubMedGoogle Scholar
  115. 115.
    Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., and Hannun, Y. A. (1993) Ceramide activates heterotrimeric protein phosphatase 2A. J. Biol. Chem. 268, 15523–15530.PubMedGoogle Scholar
  116. 116.
    Wolff, R. A., Dobrowsky, R. T., Bielawska, A., Obeid, L. M., and Hannun, Y. A. (1994) Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J. Biol. Chem. 269, 19605–19609.PubMedGoogle Scholar
  117. 117.
    Chalfant, C. E., Kishikawa, K., Mumby, M. C., Kamibayashi, C., Bielawska, A., and Hannun, Y. A. (1999) Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem. 274, 20313–20317.PubMedGoogle Scholar
  118. 118.
    Deng, X., Ito, T., Carr, B., Mumby, M., and May, W. S., Jr. (1998) Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J. Biol. Chem. 273, 34157–34163.PubMedGoogle Scholar
  119. 119.
    Ruvolo, P. P., Deng, X., Ito, T., Carr, B. K., and May, W. S. (1999) Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J. Biol. Chem. 274, 20296–20300.PubMedGoogle Scholar
  120. 120.
    Sato, S., Fujita, N., and Tsuruo, T. (2000) Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA 97, 10832–10837.PubMedGoogle Scholar
  121. 121.
    Sweeney, E. A., Inokuchi, J., and Igarashi, Y. (1998) Inhibition of sphingolipid induced apoptosis by caspase inhibitors indicates that sphingosine acts in an earlier part of the apoptotic pathway than ceramide. FEBS Lett. 425, 61–65.PubMedGoogle Scholar
  122. 122.
    Moore, A. N., Kampfl, A. W., Zhao, X., Hayes, R. L., and Dash, P. K. (1999) Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes. Neuroscience 94, 405–415.PubMedGoogle Scholar
  123. 123.
    Gennero, I., Fauvel, J., Nieto, M., Cariven, C., Gaits, F., Briand-Mesange, F., et al. (2002) Apoptotic effect of sphingosine 1-phosphate and increased sphingosine 1-phosphate hydrolysis on mesangial cells cultured at low cell density. J. Biol. Chem. 277, 12724–12734.PubMedGoogle Scholar
  124. 124.
    Pyne, S. (2002) Cellular signaling by sphingosine and sphingosine 1-phosphate. Their opposing roles in apoptosis. Subcell. Biochem. 36, 245–268.PubMedCrossRefGoogle Scholar
  125. 125.
    Cuvillier, O., Rosenthal, D. S., Smulson, M. E., and Spiegel, S. (1998) Sphingosine 1-phosphate inhibits activation of caspases that cleave phly(ADP-ribose) polymerase and lamins during Fas- and ceramide-mediated apoptosis in Jurkat T lymhocytes. J. Biol. Chem. 273, 2910–2916.PubMedGoogle Scholar
  126. 126.
    Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P. G., Coso, O. A., Gutkind, S., et al. (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803.PubMedGoogle Scholar
  127. 127.
    Castillo, S. S. and Teegarden, D. (2001) Ceramide conversion to sphingosine-1-phosphate is essential for survival in C3H10T1/2 cells. J. Nutr. 131, 2826–2830.PubMedGoogle Scholar
  128. 128.
    Morita, Y., Perez, G. I., Paris, F., Miranda, S. R., Ehleiter, D., Haimovitz-Friedman, A., et al. (2000) Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat. Med. 6, 1109–1114.PubMedGoogle Scholar
  129. 129.
    Manggau, M., Kim, D. S., Ruwisch, L., Vogler, R., Korting, H. C., Schafer-Korting, M., et al. (2001) 1Alpha,25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate. J. Invest. Dermatol. 117, 1241–1249.PubMedGoogle Scholar
  130. 130.
    Misasi, R., Sorice, M., Di Marzio, L., Campana, W. M., Molinari, S., Cifone, M. G., et al. (2001) Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase. FASEB J. 15, 467–474.PubMedGoogle Scholar
  131. 131.
    Cuvillier, O. and Levade, T. (2001) Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 98, 2828–2836.PubMedGoogle Scholar
  132. 132.
    Kwon, Y. G., Min, J. K., Kim, K. M., Lee, D. J., Billiar, T. R., and Kim, Y. M. (2001) Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J. Biol. Chem. 276, 10627–10633.PubMedGoogle Scholar
  133. 133.
    Xia, P., Wang, L., Gamble, J. R., and Vadas, M. A. (1999) Activation of sphingosine kinase by tumor necrosis factor-alpha inhibits apoptosis in human endothelial cells. J. Biol. Chem. 274, 34499–34505.PubMedGoogle Scholar
  134. 134.
    Edsall, L. C., Cuvillier, O., Twitty, S., Spiegel, S., and Milstien, S. (2001) Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J. Neurochem. 76, 1573–1584.PubMedGoogle Scholar
  135. 135.
    Strelow, A., Bernardo, K., Adam-Klages, S., Linke, T., Sandhoff, K., kronke, M., et al. (2000) Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J. Exp. Med. 192, 601–612.PubMedGoogle Scholar
  136. 136.
    Prieschl, E. E., Csonga, R., Novotny, V., Kikuchi, G. E., and Baumruker, T. (1999) The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fc epsilon receptor I triggering. J. Exp. Med. 190, 1–8.PubMedGoogle Scholar
  137. 137.
    Le Stunff, H., Galve-Roperh, I., Peterson, C., Milstien, S., and Spiegel, S. (2002) Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J. Cell Biol. 158, 1039–1049.PubMedGoogle Scholar
  138. 138.
    Le Stunff, H., Peterson, C., Liu, H., Milstien, S., and Spiegel, S. (2002) Sphingosine-1-phosphate and lipid phosphohydrolases. Biochim. Biophys. Acta 1582, 8–17.PubMedGoogle Scholar
  139. 139.
    Baumruker, T. and Prieschl, E. E. (2002) Sphingolipids and the regulation of the immune response. Semin. Immunol. 14, 57–63.PubMedGoogle Scholar
  140. 140.
    Preschl, E. E. and Baumruker, T. (2000) Beyond a structural component: sphingolipids in immunology. Arch. Immunol. Ther. Exp. (Warsz) 48, 163–171.Google Scholar
  141. 141.
    Ballou, L. R. Geramide and inflammation. In: Sphingolipid-mediated signal transduction. (Hannun, Y. A., ed), R. G. Landes Company, Austin, Texas, 1997.Google Scholar
  142. 142.
    Goldsby, R. A., Kindt, T. J., and Osborne, B. A. Kuby Immunology. W. H. Freeman and Company, New York, 2000.Google Scholar
  143. 143.
    Dinarello, C. A. (1994) Inflammatory cytokines: interleukin-1 and tumor necrosis factor as effector molecules in autoimmune disease. Curr. Opin. Immunol. 3, 941–948.Google Scholar
  144. 144.
    Dinarello, C. A. (1996) Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147.PubMedGoogle Scholar
  145. 145.
    Dinarello, C. A. (1998) Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int. Rev. Immunol. 16, 457–499.PubMedGoogle Scholar
  146. 146.
    Goetzl, E. J., An, S., and Smith, W. L. (1995) Specificity of expression and effects of eicosanoids mediators in normal physiology and human diseases. FASEB J. 9, 1051–1058.PubMedGoogle Scholar
  147. 147.
    Dbaibo, G. S., Obeid, L. M., and Hannun, Y. A. (1993) Tumor necrosis factor-alpha signal transduction through ceramide. J. Biol. Chem. 268, 17762–17766.PubMedGoogle Scholar
  148. 148.
    Kolesnick, R. and Golde, D. W. (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 77, 325–328.PubMedGoogle Scholar
  149. 149.
    Nikolova-Karakashian, M., Morgan, E. T., Alexander, C., Liotta, D. C., and Merrill, A. H., Jr. (1997) Bimodal regulation of ceramidase by interleukin-1b: implications for the regulation of cytochrome p450 2C11. J. Biol. Chem. 272, 18718–18724.PubMedGoogle Scholar
  150. 150.
    Yamamura, S., Sadahira, Y., Ruan, F., Hakomori, S., and Igarashi, Y. (1996) Sphingosine-1-phosphate inhibits actin nucleation and pseudopodium formation to control cell motility of mouse melanoma cells. FEBS Lett. 382, 193–197.PubMedGoogle Scholar
  151. 151.
    Spiegel, S., Olivera, A., Zhang, H., Thompson, E. W., Su, Y., and Berger, A. (1994) Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells. Breast Cancer Res. Treat. 31, 337–348.PubMedGoogle Scholar
  152. 152.
    Takuwa, Y., Takuwa, N., and Sugimoto, N. (2002) The edg family g proteincoupled receptors for lysophospholipids: their signaling properties and biological activities. J. Biochem. (Tokyo) 131, 767–771.Google Scholar
  153. 153.
    Goetzl, E. J., Dolezalova, H., Kong, Y., Hu, Y. L., Jaffe, R. B., Kalli, K. R., et al. (1999) Distinctive expression and functions of the type 4 endothelial differentiation geneencoded G protein-coupled receptor for lysophosphatidic acid in ovarian cancer. Cancer Res. 59, 5370–5375.PubMedGoogle Scholar
  154. 154.
    Stam, J. C., Michiels, F., van der Kammen, R. A., Moolenaar, W. H., and Collard, J. G. (1998) Invasion of T-lymphoma cells: cooperation between Rho family GTPases and lysophospholipid receptor signaling. EMBO J. 17, 4066–4074.PubMedGoogle Scholar
  155. 155.
    Wargovich, M. J. (1997) Experimental evidence for cancer preventive elements in foods. Cancer Lett. 114, 11–17.PubMedGoogle Scholar
  156. 156.
    Potter, J. D. (1996) Nutrition and colorectal cancer. Cancer Causes Control 7, 127–146.PubMedGoogle Scholar
  157. 157.
    Kim, Y. I. and Mason, J. B. (1996) Nutrition chemoprevention of gastrointestinal cancers: a critical review. Nutr. Rev. 54, 259–279.PubMedCrossRefGoogle Scholar
  158. 158.
    Mason, J. B. and Kim, Y. (1999) Nutritional strategies in the prevention of colorectal cancer. Curr. Gastroenterol. Rep. 1, 341–353PubMedGoogle Scholar
  159. 159.
    Schmelz, E. M., Crall, K. J., LaRocque, R., Dillehay, D. L., and Merrill, A. H. (1994) Uptake and metabolism of sphingolipids in isolated intestinal loops of mice. J. Nutr. 124, 701–712.Google Scholar
  160. 160.
    Schmelz, E. M., Dillehay, D. L., Webb, S. K., Reiter, A., Adams, J., and Merrill, A. H., Jr. (1996) Sphingomyelin consumption suppresses aberrant colonic crypt foci and increases the proportion of adenomas versus adenocarcinomas in CF1 mice treated with 1,2-dimethylhydrazine: implications for dietary sphingolipids and colon carcingoenesis. Cancer Res. 56, 4936–4941.PubMedGoogle Scholar
  161. 161.
    Birt, D. F., Merrill, A. H., Jr., Barnett, T., Enkvetchakul, B., Pour, P. M., Liotta, D. C., et al. (1998) Inhibition of skin carcinomas but not papillomas by sphingosine, N-methylsphingosine, and Nacetylsphingosine. Nutr Cancer 31, 119–126.PubMedCrossRefGoogle Scholar
  162. 162.
    Venable, M. E. and Obeid, L. M. (1999) Phospholipase D in cellular senescence. Biochim. Biophys. Acta 1439, 291–298.PubMedGoogle Scholar
  163. 163.
    Obeid, L. M. and Venable, M. E. (1997) Signal transduction in cellular senescence. J. Am. Geriatr. Soc. 45, 361–366.PubMedGoogle Scholar
  164. 164.
    Yechiel, E. and Barenholz, Y. (1985) Relationships between membrane lipid composition and biological properties of rat myocytes. J. Biol. Chem. 260, 9123–9131.PubMedGoogle Scholar
  165. 165.
    Miller, C. J. and Stein, G. H. (2001) Human diploid fibroblasts that undergo a senescent-like differentiation have elevated ceramide and diacylglycerol. J. Gerontol. (A) Biol. Sci. Med. Sci. 56, B8–19.Google Scholar
  166. 166.
    Venable, M. E., Lee, J. Y., Smyth, M. J., Bielawska, A., and Obeid, L. M. (1995) Role of ceramide in cellular senescence. J. Biol. Chem. 270, 30701–30708.PubMedGoogle Scholar
  167. 167.
    Mouton, R. E. and Venable, M. E. (2000) Ceramide induces expression of the senescence histochemical marker, beta-galactosidase, in human fibroblasts. Mech. Ageing Dev. 113, 169–181.PubMedGoogle Scholar
  168. 168.
    Abousalham, A., Liossis, C., O'Brien, L., and Brindley, D. N. (1997) Cell permeable ceramides prevent the activation of phospholipase D by ADP ribosylation factor and RhoA. J. Biol. Chem. 272, 1069–1075.PubMedGoogle Scholar
  169. 169.
    Nakamura, Y., Nakashima, S., Ojio, K., Banno, Y., Miyata, H., and Nozawa, Y. (1996) Ceramide inhibits IgE-mediated activation of phospholipase D, but not of phospholipase C, in rat basophilic leukemia (RBL-2H3) cells. J. Immunol. 156, 256–262.PubMedGoogle Scholar
  170. 170.
    Yoshimura, S., Sakai, H., Ohguchi, K., Nakashima, S., Banno, Y., Nishimura, Y., et al. (1997) Changes in the activity and mRNA levels of phospholipase D during ceramide-induced apoptosis in rat C6 glial cells. J. Neurochem. 69, 713–720.PubMedCrossRefGoogle Scholar
  171. 171.
    Tilly, J. L. and Kolesnick, R. N. (1999) Sphingolipid signaling in gonadal development and function. Chem. Phys. Lipids 102, 149–155.PubMedGoogle Scholar
  172. 172.
    Ghosh, S., Strum, J. C., and Bell, R. M. (1997) Lipid biochemistry: functions of glycerolipids and sphingolipids in cellular signaling. FASEB J. 11, 45–50.PubMedGoogle Scholar
  173. 173.
    Strum, J. C., Swenson, K. I., and Bell, R. M. A role for ceramide in meiosis. In: Sphingolipid-Mediated Signal Transduction. (Hannun, Y. A., ed.), R. G. Landes Company, Austin, Texas, 1997, pp. 53–60.Google Scholar
  174. 174.
    Morrill, G. A. and Kostellow, A. B. (1998) Progesterone release of lipid second messengers at the amphibian oocyte plasma membrane: role of ceramide in initiating the G2/M transition. Biochem. Biophys. Res. Commun. 246, 359–363.PubMedGoogle Scholar
  175. 175.
    Varnold, R. L. and Smith, L. D. (1990) Protein kinase C and progesterone-induced maturation in Xenopus oocytes. Development 109, 597–604.PubMedGoogle Scholar
  176. 176.
    Strum, J. C., Swenson, K. I., Turner, J. E., and Bell, R. M. (1995) Ceramide triggers meiotic cell cycle progression in Xenopus oocytes: a potential mediator of progesterone-induced maturation. J. Biol. Chem. 270, 13541–13547.PubMedGoogle Scholar
  177. 177.
    De Smedt, V., Rime, H., Jessus, C., and Ozon, R. (1995) Inhibition of glycoaphingolipid synthesis induces p34cdc2 activation in Xenopus oocyte. FEBS Lett. 375, 249–253.PubMedGoogle Scholar
  178. 178.
    Lin, T. Y., Viswanathan, S., Wood, C., Wilson, P. G., Wolf, N., and Fuller, M. T. (1996) Coordinate developmental control of the meiotic cell cycle and spermatid differentiation in Drosophila males. Development 122, 1331–1341.PubMedGoogle Scholar
  179. 179.
    Endo, K., Akiyama, T., Kobayashi, S., and Okada, M. (1996) Degenerative spermatocyte, a novel gene encoding a transmembrane protein required for the initiation of meiosis in Drosophila spermatogenesis. Mol. Gen. Genet. 253, 157–165.PubMedGoogle Scholar
  180. 180.
    Endo, K., Matsuda, Y., and Kobayashi, S. (1997) Mdes, a mouse homolog of the Drosophila degenerative spermatocyte gene is expressed during mouse spermatogenesis. Dev. Growth Differ. 39, 399–403.PubMedGoogle Scholar
  181. 181.
    Bielawska, A., Crane, H. M., Liotta, D., Obeid, L. M., and Hannun, Y. A. (1993) Selectivity of ceramide-mediated biology. Lack of activity of erythrodihydroceramide. J. Biol. Chem. 268, 26226–26232.PubMedGoogle Scholar
  182. 182.
    Michel, C., van Echten-Deckert, G., Rother, J., Sandhoff, K., Wang, E., and Merrill, A. H., Jr., (1997) Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J. Biol. Chem. 272, 22432–22437.PubMedGoogle Scholar
  183. 183.
    Sax, C. M. and Piatigorsky, J. (1994) Expression of the alpha-crystallin/small heat-shock protein/molecular chaperone genes in the lens and other tissues. Adv. Enzymol. Relat. Areas Mol. Biol. 69, 155–201.PubMedGoogle Scholar
  184. 184.
    Shyman, J. A. and Radin, N. S. The use of cerebroside synthase inhibitors as probes for assessing the metabolism and function of sphingolipids. In: Sphingolipid-Mediated Signal Transduction. (Hannun, Y. A., ed.), R. G. Landes Company, Austin, Texas, 1997, pp. 91–102.Google Scholar
  185. 185.
    Chang, Y., Abe, A., and Shayman, J. A. (1995) Ceramide formation during heat shock: a potential mediator of alpha B-crystallin transcription. Proc. Natl. Acad. Sci. USA, 92, 12275–12279.PubMedGoogle Scholar
  186. 186.
    Ferguson-Yankey, S. R., Skrzypek, M. S., Lester, R. L., and Dickson, R. C. (2002) Mutant analysis reveals complex regulation of sphin-golipid long chain base phosphates and long chain bases during heat stress in yeast. Yeast 19, 573–586.PubMedGoogle Scholar
  187. 187.
    Skrzypek, M. S., Nagiec, M. M., Lester, R. L., and Dickson, R. C. (1999) Analysis of phosphorylated sphingolipid long-chain bases reveals potential roles in heat stress and growth control in Saccharomyces. J. Bacteriol. 181, 1134–1140.PubMedGoogle Scholar
  188. 188.
    Jenkins, G. M., Richards, A., Wahl, T., Mao, C., Obeid, L., and Hannun, Y. (1997) Involvement of yeast sphingolipids in the heat stress response of Saccharomyces cerevisiae. J. Biol. Chem. 272, 32566–32572.PubMedGoogle Scholar
  189. 189.
    Dickson, R. C., Nagiec, E. E., Skrzypek, M., Tillman, P., Wells, G. B., and Lester, R. L. (1997) Sphingolipids are potential heat stress signals in Saccharomyces. J. Biol. Chem. 272, 30196–30200.PubMedGoogle Scholar
  190. 190.
    Wells, G. B., Dickson, R. C. and Lester, R. L. (1998) Heat-induced elevation of ceramide in Saccharomyces cerevisiae via de novo synthesis. J. Biol. Chem. 273, 7235–7243.PubMedGoogle Scholar
  191. 191.
    Jenkins, G. M., Cowart, L. A., Signorelli, P., Pettus, B. J., Chalfant, C. E., and Hannun, Y. A. (2002) Acute activation of de novo sphin-golipid biosynthesis upon heat shock causes an accumulation of ceramide and subsequent dephosphorylation of SR proteins. J. Biol. Chem. 277, 42572–42578.PubMedGoogle Scholar
  192. 192.
    Kondo, T., Matsuda, T., Kitano, T., Takahashi, A., Tashima, M., Ishikura, H., et al. (2000) Role of c-jun expression increased by heat shock-and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosis. J. Biol. Chem. 275, 7668–7676.PubMedGoogle Scholar
  193. 193.
    Verheij, M., Bose, R., Lin, X. H., Yao, B., Jarvis, W. D., Grant, S., et al. (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380, 75–79.PubMedGoogle Scholar
  194. 194.
    Huang, C., Ma, W., Ding, M., Bowden, G. T., and Dong, Z. (1997) Direct evidence for an important role of sphingomyelinase in ultraviolet-induced activation of c-Jun N-terminal kinase. J. Biol. Chem. 272, 27753–27757.PubMedGoogle Scholar
  195. 195.
    Grether-Beck, S., Bonizzi, G., Schmitt-Brenden, H., Felsner, I., Timmer, A., Sies, H., et al. (2000) Non-enzymatic triggering of the ceramide signalling cascade by solar UVA radiation, EMBO J. 19, 5793–5800.PubMedGoogle Scholar
  196. 196.
    Chatterjee, M. and Wu, S. (2001) Cell line dependent involvement of ceramide in ultraviolet light-induced apoptosis. Mol. Cell. Biochem. 219, 21–27.PubMedGoogle Scholar
  197. 197.
    Holleran, W. M., Uchida, Y., Halkier-Sorensen, L., Haratake, A., Hara, M., Epstein, J., et al. (1997) Structural basis for the UVB-induced abnormality in epidermal barrier function. Photodermatol. Photoimmunol. Photomed. 13, 117–128.PubMedGoogle Scholar
  198. 198.
    Farrell, A. M., Uchida, Y., Nagie, M. M., Harris, I. R., Dickson, R. C., Elias, P. M., et al. (1998) UVB irradiation up-regulates serine palmitoyltransferase in cultured human keratinocytes. J. Lipids Res. 39, 2031–2038.Google Scholar
  199. 199.
    Deng, J., Zhang, H., Kloosterboer, F., Liao, Y., Klostergaard, J., Levitt, M. L., et al. (2002) Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis. Oncogene 21, 44–52.PubMedGoogle Scholar
  200. 200.
    Verheij, M., van Blitterswijk, W. J., and Bartelink, H. (1998) Radiation-induced apoptosis—the ceramide-SAPK signaling pathway and clinical aspects. Acta Oncol. 37, 575–581.PubMedGoogle Scholar
  201. 201.
    Watters, D. (1999) Molecular mechanisms of ionizing radiation-induced apoptosis. Immunol. Cell. Biol. 77, 263–271.PubMedGoogle Scholar
  202. 202.
    Schmidt-Ullrich, R. K., Dent, P., Grant, S., Mikkelsen, R. B., and Valerie, K. (2000) Signal transduction and cellular radiation responses. Radiat. Res. 153, 245–257.PubMedGoogle Scholar
  203. 203.
    Haimovitz-Friedman, A., Kolesnick, R. N., and Fuks, Z. (1997) Differential inhibition of radiation-induced apoptosis. Stem Cells 15, 43–47.PubMedCrossRefGoogle Scholar
  204. 204.
    Haimovitz-Friedman, A., Kan, C. C., Ehleiter, D., Persanud, R. S., McLoughlin, M., Fuks, Z., et al. (1994) Ionizing radiation acts on cellular membranes to generate ceramid and initiate apoptosis. J. Exp. Med. 180, 525–535.PubMedGoogle Scholar
  205. 205.
    Fuks, Z., Haimovitz-Friedman, A., and Kolesnick, R. N. (1995) The role of the sphingomyelin pathway in radiation-induced cell kill. Important Adv. Oncol. 9, 19–31.Google Scholar
  206. 206.
    Michael, J. M., Lavin, M. F., and Watters, D. J. (1997) Resistance to radiation-induced apoptosis in Burkitt's lymphoma cells is associated with defective ceramide signaling. Cancer Res. 57, 3600–3605.PubMedGoogle Scholar
  207. 207.
    Chmura, S. J., Mauceri, H. J., Advani, S., Heimann, R., Beckett, M. A., Nodzenski, E., et al. (1997) Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation. Cancer Res. 57, 4340–4347.PubMedGoogle Scholar
  208. 208.
    Santana, P., Pena, L. A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., et al. (1996) Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189–199.PubMedGoogle Scholar
  209. 209.
    Bruno, A. P., Laurent, G., Averbeck, D., Demur, C., Bonnet, J., Bettaieb, A., et al. (1998) Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation. Cell Death Differ. 5, 172–182.PubMedGoogle Scholar
  210. 210.
    Chmura, S. J., Nodzenski, E., Kharbanda, S., Pandey P., Quintans, J., Kufe, D. W. et al. (2000) Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis. Mol. Pharmacol. 57, 792–796.PubMedGoogle Scholar
  211. 211.
    Grant, S. (1997) 1-[b-D-arabinofuranosyl]cytosine: molecular and cellular pharmacology. Adv. Cancer Res. 72, 197–233.Google Scholar
  212. 212.
    Mayer, R. J., Davis, R. B., Schiffer, C. A., Berg, D. T., Powell, B. L., Schulman, P., et al. (1994) Intensive postremisson chemotherapy in adults with acute myeloid leukemia. Cancer and leukemia group B. New Engl. J. Med. 331, 896–903.PubMedGoogle Scholar
  213. 213.
    Gunji, H., Kharbanda, S., and Kufe, D. (1991) Induction of internucleosomal DNA fragmentation in human myeloid leukemia cells by 1-beta-darabinofuranosylcytosine. Cancer Res. 51, 741–743.PubMedGoogle Scholar
  214. 214.
    Kufe, D., Spriggs, D., Egan, E. M., and Munroe, D. (1984) Relationships among Ara-CTP pools, formation of (Ara-C) DNA, and cytotoxicity of human leukemic cells. Blood 64, 54–58.PubMedGoogle Scholar
  215. 215.
    Strum, J. C., Small, G. W., Pautig, S. B., and Daniel, L. W. (1994) 1-beta-d- arabinofuranosylcytosine stimulates ceramides and diglyceride formation in HL-60 cells. J. Biol. Chem. 269, 15493–15497.PubMedGoogle Scholar
  216. 216.
    Grant, S., Freemerman, A. J., Birrer, M. J., Martin, H. A., Turner, A. J., Szabo, E., et al. (1996) Effect of 1-[b-D-arabinofuranosyl]cytosine on apoptosis and differentiation in human monoblastic leukemia cells (U937) expressing a c-Jun dominant-negative mutant protein (TAM-67). Cell Death Differ. 7, 603–613.Google Scholar
  217. 217.
    Hande, K. R. (1998) Clinical applications of anticancer drugs targeted to topoisomerase II. Biochim. Biophys. Acta 1400, 173–184.PubMedGoogle Scholar
  218. 218.
    Jaffrezou, J.-P., Levade, T., Bettaieb, A., Andrieu, N., Bezombes, C., Maestre, N., et al., (1996). Daunorubicin-induced apoptosis: triggering ceramide generation through sphingomyelin hydrolysis. EMBO J. 15, 2417–2424.PubMedGoogle Scholar
  219. 219.
    Bose, R., Verheij, M., Haimovitz-Friedman, A., Scotto, K., and Kolesnick, R. N. (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell Death Differ. 82, 405–414.Google Scholar
  220. 220.
    Allouche, M., Bettaieb, A., Vindis, C., Rousse, A., Gringon, C., and Laurent, G. (1997) Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells. Oncogene 14, 1837–1845.PubMedGoogle Scholar
  221. 221.
    Mansat, V., Bettaieb, A., Levade, T., Laurent, G., and Jaffrezou, J. P. (1997) Serine protease inhibitors block neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered by daunorubicin. FASEB J. 11, 695–702.PubMedGoogle Scholar
  222. 222.
    Mansat, V., Laurent, G., Levade, T., Bettaieb, A., and Jaffrezou, J. P. (1997) The protein kinase C activators phorbol diesters and phosphatidylserine inhibit neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered by daunorubicin. Cancer Res. 57, 5300–5304.PubMedGoogle Scholar
  223. 223.
    Hande, K. R. (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer 34, 1514–1521.PubMedGoogle Scholar
  224. 224.
    Tepper, A. D., de Vries, E., van Blitterswijk, W. J., and Borst, J. (1999) Ordering of ceremide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage-induced apoptosis. J. Clin. Invest. 103, 971–978.PubMedGoogle Scholar
  225. 225.
    Perry, D. K., Carton, J., Shah, A. K., Meredith, F., Uhlinger, D. J., and Hannun, Y. A. (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem. 275, 9078–9084.PubMedGoogle Scholar
  226. 226.
    Duerksen-Hughes, P., Yang, J., and Schwartz S. B. (1999) HPV16E6 blocks TNF-mediated apoptosis in mouse fibroblast LM cells. Virology 264, 55–65.PubMedGoogle Scholar
  227. 227.
    Nikolova-Karakashian, M., Vales, T. R., Wang, E., Menaldino, D. S., Alexander, C., Goh, J., et al. Ceramide synthase and ceramidases in the regulation of sphingoid base metabolism. In: Sphingolipid-Mediated Signal Transduction. (Hannun, Y. A., ed.), R. G. Landes Company, Austin, Texas, 1997, pp. 159–172.Google Scholar
  228. 228.
    Blazquez, C., Geelen, M. J., Velasco, G., and Guzman, M. (2001) The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes. FEBS Lett. 489, 149–153.PubMedGoogle Scholar
  229. 229.
    Mandala, S. M. and Harris, G. H. (2000) Isolaton and characterization of novel inhibitors of sphingolipid synthesis: australifungin, viridiofungins, rustmicin, and khafrefungin. Methods Enzymol. 311, 335–348.PubMedGoogle Scholar
  230. 230.
    Kiuchi, M., Adachi, K., Kohara, T., Minoguchi, M., Hanano, T., Aoki, Y., et al. (2000) Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J. Med. Chem. 43, 2946–2961.PubMedGoogle Scholar
  231. 231.
    Riely, R. T., Norred, W. P., Wang, E., and Merrill, A. H., Jr. (1999) Alteration in sphingolipid metabolism: bioassays for fumonisinand ISP-1-like activity in tissues cells and other matrices. Nat. Toxins 7, 407–414.Google Scholar
  232. 232.
    Linn, S. C., Kim, H. S., Keane, E. M., Andras, L. M., Wang, E., and Merrill, A. H., Jr. (2001) Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption. Biochem. Soc. Trans. 29, 831–835.PubMedGoogle Scholar
  233. 233.
    Merrill, A. H., Jr., Sullards, M. C., Wang, E., Voss, K. A., and Riely, R. T. (2001) Sphingolipid metabolism: roles in signal transduction and disruption by fumonisin. Environ. Health Perspect. 109, 283–289.PubMedGoogle Scholar
  234. 234.
    Merrill, A. H. J., Liotta, D. C., and Riley, R. T. (1996) Fumonisins: fungal toxins that shed light on sphingolipid function. Trends Cell Biol. 6, 218–223.PubMedGoogle Scholar
  235. 235.
    Humpf, H. U., Schmelz, E. M., Meredith, F. I., Vesper, H., Vales, T. R., Wang, E., et al. (1998) 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. 273, 19060–19064.PubMedGoogle Scholar
  236. 236.
    Desai, K., Sullards, M. C., Allegood, J., Wang, E., Schmelz, E. M., Hartl, M., et al. (2002) Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis. Biochim. Biophys. Acta 1585, 188–192.PubMedGoogle Scholar
  237. 237.
    Riely, R. T., Enongene, E., Voss, K. A., Norred, W. P., Meredith, F. I., Sharma, R. P., et al. (2001) Sphingolipid perturbations as mechanisms for fumonisin carcinogenesis. Environ. Health Perspect. 109, 301–308.Google Scholar
  238. 238.
    Abne, C. C., Borkowf, C. B., Qiao, Y. L., Albert, P. S., Wang, E., Merrill, A. H., Jr., et al. (2001) Sphingolipids as biomarkers of fumonisin exposure and risk of esophageal squamous cell carcinoma in China. Cancer Cause Control 12, 821–828.Google Scholar
  239. 239.
    Rani, C. S., Abe, A., Chang, Y., Rosenzweig, N., Saltiel, A. R., Radin, N. S. et al. (1995) Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. J. Biol. Chem. 270, 2859–2867.PubMedGoogle Scholar
  240. 240.
    Shayman, J. A., Mahdiyoun, S., Deshmukh, G., Barcelon, F., Inokuchi, J., and Radin, N. S. (1990) Glucosphingolipid dependence of hormone-stimulated inositol trisphosphate formation. J. Biol. Chem. 265, 12135–12138.PubMedGoogle Scholar
  241. 241.
    Olshefski, R. and Ladisch S. (1998) Synthesis shedding, and intercellular transfer of human medulloblastoma gangliosides: abrogation by a new inhibitor of glucosylceramide synthase. J. Neurochem. 70, 467–472.PubMedCrossRefGoogle Scholar
  242. 242.
    di Bartolomeo, S. and Spinedi, A. (2001) Differential chemosensitizing effect of two glucosylceramide: synthase inhibitors in hepatoma cells. Biochem. Biophys. Res. Commun. 288, 269–274.PubMedGoogle Scholar
  243. 243.
    Levade, T., Andrieu-Abadie, N., Segui, B., Auge, N., Chatelut, M., Jaffrezou, J. P., et al. (1999) Sphingomyelin-degrading pathways in human cells: role in cell signalling. Chem. Physics Lipids 102, 167–178.Google Scholar
  244. 244.
    Chatterjee, S. (1993) Neutral sphingomyelinase. Adv. Lipid Res. 26, 25–47.PubMedGoogle Scholar
  245. 245.
    Okazaki, T., Bielawska, A., Domane, N., Bell, R. M., and Hannun, Y. A. (1994) Characteristics and partial purification of a novel cytosolic, magnesium independent, neutral sphingomyelinase activated in the early signal transduction of 1a, 25-dihydorxyvitamin D3-induced HL-60 cell differentiation. J. Biol. Chem. 269, 4070–4077.PubMedGoogle Scholar
  246. 246.
    Spence, M. W. (1993) Sphingomyelinases. Adv. Lipid Res. 26, 3–23.PubMedGoogle Scholar
  247. 247.
    Schmuth, M., Man, M. Q., Weber, F., Gao, W., Feingold, K. R., Fritsch, P., et al. (2000) Permeability barrier disorder in Niemann-Pick disease: sphingomyelin-ceramide processing required for normal barrier homeostasis. J. Invest. Dermatol. 115, 459–466.PubMedGoogle Scholar
  248. 248.
    Hauck, C. R., Grassme, H., Bock, J., Jendrossek, V., Ferlinz, K., Meyer, T. F., et al. (2000) Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett. 478, 260–266.PubMedGoogle Scholar
  249. 249.
    Hurwitz, R., Ferlinz, K., and Sandhoff, K. (1994) The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol. Chem. Hoppe Seyler 375, 447–450.PubMedGoogle Scholar
  250. 250.
    Uchida, R., Tomoda, H., Arai, M., and Omura, S. (2001) Chlorogentisylquinone, a new neutral sphingomyelinase inhibitor, produced by a marine fungus. J. Antibiot. (Tokyo) 54, 882–889.Google Scholar
  251. 251.
    Nara, F., Tanaka, M., Masuda-Inoue, S., Yamasato, Y., Doi-Yoshioka, H., Suzuki-Konagai, et al. (1999) Biological activities of scyphostatin, a neutral sphingomyelinase inhibitor from a discomycete, Trichopeziza mollissima. J. Antibiot. (Tokyo) 52, 531–535.Google Scholar
  252. 252.
    Arenz, C., Gartner, M., Wascholowski, V., and Giannis, A. (2001) Synthesis and biochemical investigation of scyphostatin analogues as inhibitors of neutral sphingomyelinase. Bioorg. Med. Chem. 9, 2901–2904.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Jun Yang
    • 1
    • 2
  • Yingnian Yu
    • 1
    • 2
  • Shuyu Sun
    • 3
  • Penelope J. Duerksen-Hughes
    • 4
  1. 1.Department of Pathology and PathophysiologyZhejiang University School of MedicineHangzhouChina
  2. 2.Department of Public HealthZhejiang University School of MedicineHangzhouChina
  3. 3.The Affiliated HospitalShandong UniversityJinan, ShandongChina
  4. 4.Department of Biochemistry and Microbiology, Center for Molecular Biology and Gene TherapyLoma Linda University School of MedicineLoma Linda

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