Ceramide and apoptosis: Exploring the enigmatic connections between sphingolipid metabolism and programmed cell death

Anti-Cancer Agents in Medicinal Chemistry

Volumn 12, Issue 4, 2012, Pages 340-363

  Mullen, Thomas D ^b   Obeid, Lina M ^a,b  

^a RALPH H JOHNSON VA MEDICAL CENTER   (United States)

^b MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

Author keywords

Apoptosis; Ceramide; Ceramide synthase; De novo sphingolipid synthesis; Programmed cell death; Salvage pathway; Serine palmitoyl transferase; Sphingomyelinase

Indexed keywords

ADENOSINE TRIPHOSPHATE; CARNITINE PALMITOYLTRANSFERASE; CASPASE; CASPASE 8; CATHEPSIN D; CERAMIDASE; CERAMIDE; CERAMIDE GLUCOSYLTRANSFERASE; CURCUMIN; CYCLOHEXIMIDE; INTERLEUKIN 1; MITOGEN ACTIVATED PROTEIN KINASE; PEPSTATIN; PROTEIN BCL 2; RECEPTOR INTERACTING PROTEIN 140; SPHINGOLIPID; SPHINGOMYELIN PHOSPHODIESTERASE; TUMOR NECROSIS FACTOR ALPHA;

APOPTOSIS; AUTOPHAGY; CELL PERMEABILIZATION; ENZYME ACTIVATION; HUMAN; IN VIVO STUDY; LIPID METABOLISM; LIPOGENESIS; MITOCHONDRIAL MEMBRANE; NONHUMAN; PROTEIN LOCALIZATION; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION;

EID: 84860507660     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/187152012800228661     Document Type: Review

References (269)

1. Kroemer, G.; Galluzzi, L.; Vandenabeele, P.; Abrams, J.; Alnemri, E. S.; Baehrecke, E. H.; Blagosklonny, M. V.; El-Deiry, W. S.; Golstein, P.; Green, D. R.; Hengartner, M.; Knight, R. A.; Kumar, S.; Lipton, S. A.; Malorni, W.; Nunez, G.; Peter, M. E.; Tschopp, J.; Yuan, J.; Piacentini, M.; Zhivotovsky, B.; Melino, G., Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ., 2009, 16 (1), 3-11.
2. Kerr, J. F.; Wyllie, A. H.; Currie, A. R., Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer, 1972, 26 (4), 239-257.
3. Silva, M. T., Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Letters, 2010, 584 (22), 4491-4499.
4. Lemasters, J. J., Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology, 2005, 129 (1), 351-360.
5. Tait, S. W.; Green, D. R., Caspase-independent cell death: leaving the set without the final cut. Oncogene, 2008, 27 (50), 6452-6461.
6. Jaattela, M., Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene, 2004, 23 (16), 2746-2756.
7. Barnhart, B. C.; Alappat, E. C.; Peter, M. E., The CD95 type I/type II model. Semin. Immunol., 2003, 15 (3), 185-193.
8. Scaffidi, C.; Fulda, S.; Srinivasan, A.; Friesen, C.; Li, F.; Tomaselli, K. J.; Debatin, K. M.; Krammer, P. H.; Peter, M. E., Two CD95 (APO-1/Fas) signaling pathways. Embo J., 1998, 17 (6), 1675-1687.
9. Li, H.; Zhu, H.; Xu, C. J.; Yuan, J., Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell, 1998, 94 (4), 491-501.
10. Gross, A.; Yin, X. M.; Wang, K.; Wei, M. C.; Jockel, J.; Milliman, C.; Erdjument-Bromage, H.; Tempst, P.; Korsmeyer, S. J., Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J. Biol. Chem., 1999, 274 (2), 1156-1163.
11. Korsmeyer, S. J.; Wei, M. C.; Saito, M.; Weiler, S.; Oh, K. J.; Schlesinger, P. H., Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000, 7 (12), 1166-1173.
12. Danial, N. N.; Korsmeyer, S. J., Cell death: critical control points. Cell 2004, 116 (2), 205-219.
13. Yee, K. S.; Vousden, K. H., Complicating the complexity of p53. Carcinogenesis, 2005, 26 (8), 1317-1322.
14. Szegezdi, E.; Logue, S. E.; Gorman, A. M.; Samali, A., Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep., 2006, 7 (9), 880-885.
15. Brenner, C.; Grimm, S., The permeability transition pore complex in cancer cell death. Oncogene, 2006, 25 (34), 4744-4756.
16. Antonsson, B.; Martinou, J. C., The Bcl-2 protein family. Exp. Cell Res., 2000, 256 (1), 50-57.
17. Kinnally, K. W.; Antonsson, B., A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis, 2007.
18. Fulda, S.; Debatin, K. M., Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene, 2006, 25 (34), 4798-4811.
19. Braun, P. E.; Snell, E. E., Biosynthesis of sphingolipid bases. II. Keto intermediates in synthesis of sphingosine and dihydrosphingosine by cell-free extracts of Hansenula ciferri. J. Biol. Chem., 1968, 243 (14), 3775-3783.
20. Merrill, A. H., Jr., Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells. Biochim Biophys Acta 1983, 754 (3), 284-291.
21. Hanada, K., Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim. Biophys. Acta, 2003, 1632 (1-3), 16-30.
22. Braun, P. E.; Morell, P.; Radin, N. S., Synthesis of C18-and C20-dihydrosphingosines, ketodihydrosphingosines, and ceramides by microsomal preparations from mouse brain. J. Biol. Chem., 1970, 245 (2), 335-341.
23. Weiss, B.; Stoffel, W., Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur. J. Biochem., 1997, 249 (1), 239-247.
24. Hornemann, T.; Richard, S.; Rutti, M. F.; Wei, Y.; von Eckardstein, A., Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. J. Biol.Chem., 2006, 281 (49), 37275-37281.
25. Mandon, E. C.; Ehses, I.; Rother, J.; van Echten, G.; Sandhoff, K., Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver. J. Biol. Chem., 1992, 267 (16), 1118-11144.
26. Hornemann, T.; Penno, A.; Rutti, M. F.; Ernst, D.; Kivrak-Pfiffner, F.; Rohrer, L.; von Eckardstein, A., The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J. Biol. Chem., 2009, 284 (39), 26322-26330.
27. Beeler, T.; Bacikova, D.; Gable, K.; Hopkins, L.; Johnson, C.; Slife, H.; Dunn, T., The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Delta mutant. J.Biol. Chem., 1998, 273 (46), 30688-30694.
28. Pewzner-Jung, Y.; Ben-Dor, S.; Futerman, A. H., When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J. Biol. Chem., 2006, 281 (35), 25001-25005.
29. Ong, D. E.; Brady, R. N., In vivo studies on the introduction of the 4-t-double bond of the sphingenine moiety of rat brain ceramides. J. Biol. Chem., 1973, 248 (11), 3884-3888.
30. Geeraert, L.; Mannaerts, G. P.; van Veldhoven, P. P., Conversion of dihydroceramide into ceramide: involvement of a desaturase. Biochem. J., 1997, 327 (Pt 1), 125-132.
31. Ternes, P.; Franke, S.; Zahringer, U.; Sperling, P.; Heinz, E., Identification and characterization of a sphingolipid delta 4-desaturase family. J. Biol. Chem., 2002, 277 (28), 25512-25518.
32. Omae, F.; Miyazaki, M.; Enomoto, A.; Suzuki, M.; Suzuki, Y.; Suzuki, A., DES2 protein is responsible for phytoceramide biosynthesis in the mouse small intestine. Biochem. J.,2004, 379 (Pt 3), 687-695.
33. Mizutani, Y.; Kihara, A.; Igarashi, Y., Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation. FEBS Lett., 2004, 563 (1-3), 93-97.
34. Okabe, K.; Keenan, R. W.; Schmidt, G., Phytosphingosine groups as quantitatively significant components of the sphingolipids of the mucosa of the small intestines of some mammalian species. Biochem. Biophys. Res. Commun., 1968, 31 (1), 137-143.
35. Carter, H. E.; Hirschberg, C. B., Phytosphingosines and branched sphingosines in kidney. Biochemistry, 1968, 7 (6), 2296-2300.
36. Ullman, M. D.; Radin, N. S., The enzymatic formation of sphingomyelin from ceramide and lecithin in mouse liver. J. Biol. Chem., 1974, 249 (5), 1506-1512.
37. Huitema, K.; van den Dikkenberg, J.; Brouwers, J. F.; Holthuis, J. C., Identification of a family of animal sphingomyelin synthases. Embo J., 2004, 23 (1), 33-44.
38. Villani, M.; Subathra, M.; Im, Y. B.; Choi, Y.; Signorelli, P.; Del Poeta, M.; Luberto, C., Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. Biochem. J., 2008, 414 (1), 31-41.
39. Ding, T.; Li, Z.; Hailemariam, T.; Mukherjee, S.; Maxfield, F. R.; Wu, M. P.; Jiang, X. C., SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. J. Lipid Res., 2008, 49 (2), 376-385.
40. Fahy, E.; Subramaniam, S.; Brown, H. A.; Glass, C. K.; Merrill, A. H., Jr.; Murphy, R. C.; Raetz, C. R.; Russell, D. W.; Seyama, Y.; Shaw, W.; Shimizu, T.; Spener, F.; van Meer, G.; VanNieuwenhze, M. S.; White, S. H.; Witztum, J. L.; Dennis, E. A., A comprehensive classification system for lipids. J. Lipid Res., 2005, 46 (5), 839-861.
41. Basu, S.; Kaufman, B.; Roseman, S., Enzymatic synthesis of ceramide-glucose and ceramide-lactose by glycosyltransferases from embryonic chicken brain. J. Biol. Chem., 1968, 243 (21), 5802-5804.
42. Ichikawa, S.; Sakiyama, H.; Suzuki, G.; Hidari, K. I.; Hirabayashi, Y., Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc. Natl. Acad. Sci. USA, 1996, 93 (22), 12654.
43. Ichikawa, S.; Hirabayashi, Y., Glucosylceramide synthase and glycosphingolipid synthesis. Trends Cell Biol.,1998, 8 (5), 198-202.
44. Schulte, S.; Stoffel, W., Ceramide UDPgalactosyltransferase from myelinating rat brain: purification, cloning, and expression. Proc Natl. Acad. Sci. USA 1993, 90 (21), 10265-10269.
45. Suzuki, K.; Vanier, M. T.; Coetzee, T.; Popko, B., Drastically abnormal gluco-and galactosylceramide composition does not affect ganglioside metabolism in the brain of mice deficient in galactosylceramide synthase. Neurochem. Res., 1999, 24 (4), 471-474.
46. Schaeren-Wiemers, N.; van der Bijl, P.; Schwab, M. E., The UDP-galactose:ceramide galactosyltransferase: expression pattern in oligodendrocytes and Schwann cells during myelination and substrate preference for hydroxyceramide. J. Neurochem., 1995, 65 (5), 2267-2278.
47. Goni, F. M.; Alonso, A., Sphingomyelinases: enzymology and membrane activity. FEBS Lett., 2002, 531 (1), 38-46.
48. Smith, E. L.; Schuchman, E. H., The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. Faseb J., 2008, 22 (10), 3419-3431.
49. Brady, R. O.; Kanfer, J. N.; Mock, M. B.; Fredrickson, D. S., The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick diseae. Proc. Nat. Acad. Sci. USA 1966, 55 (2), 366-369.
50. Clarke, C. J.; Snook, C. F.; Tani, M.; Matmati, N.; Marchesini, N.; Hannun, Y. A., The extended family of neutral sphingomyelinases. Biochemistry, 2006, 45 (38), 11247-11256.
51. Sawai, H.; Domae, N.; Nagan, N.; Hannun, Y. A., Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. J. Biol. Chem., 1999, 274 (53), 38131-38139.
52. Tani, M.; Hannun, Y. A., Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Lett., 2007, 581 (7), 1323-1328.
53. Duan, R. D., Alkaline sphingomyelinase: an old enzyme with novel implications. Biochim. Biophys. Acta, 2006, 1761 (3), 281-291.
54. Duan, R. D.; Nyberg, L.; Nilsson, A., Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. Biochim. Biophys. Acta., 1995, 1259 (1), 49-55.
55. Schulze, H.; Kolter, T.; Sandhoff, K., Principles of lysosomal membrane degradation: Cellular topology and biochemistry of lysosomal lipid degradation. Biochim. Biophys. Acta, 2009, 1793 (4), 674-683.
56. Futerman, A. H.; van Meer, G., The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol., 2004, 5 (7), 554-565.
57. Brady, R. O.; Kanfer, J. N.; Shapiro, D., Metabolism of Glucocerebrosides. Ii. Evidence of an Enzymatic Deficiency in Gaucher's Disease. Biochem. Biophys. Res. Commun., 1965, 18, 221-225.
58. Mao, C.; Obeid, L. M., Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim. Biophys. Acta., 2008, 1781 (9), 424-434.
59. Tani, M.; Igarashi, Y.; Ito, M., Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu. J. Biol. Chem., 2005.
60. Kono, M.; Dreier, J. L.; Ellis, J. M.; Allende, M. L.; Kalkofen, D. N.; Sanders, K. M.; Bielawski, J.; Bielawska, A.; Hannun, Y. A.; Proia, R. L., Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J. Biol. Chem., 2006, 281 (11), 7324-7331.
61. Okino, N.; He, X.; Gatt, S.; Sandhoff, K.; Ito, M.; Schuchman, E. H., The reverse activity of human acid ceramidase. J. Biol. Chem., 2003, 278 (32), 29948-29953.
62. Mao, C.; Xu, R.; Szulc, Z. M.; Bielawski, J.; Becker, K. P.; Bielawska, A.; Galadari, S. H.; Hu, W.; Obeid, L. M., Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase: an enzyme that preferentially regulates metabolism of very long chain ceramides. J. Biol. Chem., 2003, 278 (33), 31184-31191.
63. Sun, W.; Jin, J.; Xu, R.; Hu, W.; Szulc, Z. M.; Bielawski, J.; Obeid, L. M.; Mao, C., Substrate specificity, membrane topology, and activity regulation of human alkaline ceramidase 2 (ACER2). J. Biol. Chem., 285 (12), 8995-9007.
64. Mao, C.; Xu, R.; Szulc, Z. M.; Bielawska, A.; Galadari, S. H.; Obeid, L. M., Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide. J. Biol. Chem., 2001, 276 (28), 26577-26588.
65. Hait, N. C.; Oskeritzian, C. A.; Paugh, S. W.; Milstien, S.; Spiegel, S., Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim. Biophys. Acta, 2006, 1758 (12), 2016-2026.
66. Igarashi, N.; Okada, T.; Hayashi, S.; Fujita, T.; Jahangeer, S.; Nakamura, S., Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J. Biol. Chem. 2003, 278 (47), 46832-46839.
67. Hait, N. C.; Sarkar, S.; Le Stunff, H.; Mikami, A.; Maceyka, M.; Milstien, S.; Spiegel, S., Role of sphingosine kinase 2 in cell migration toward epidermal growth factor. J. Biol. Chem., 2005, 280 (33), 29462-29469.
68. Le Stunff, H.; Giussani, P.; Maceyka, M.; Lepine, S.; Milstien, S.; Spiegel, S., Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J. Biol. Chem., 2007, 282 (47), 34372-83430.
69. Fyrst, H.; Saba, J. D., Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight. Biochim. Biophys. Acta, 2008, 1781 (9), 448-458.
70. Badiani, K.; Byers, D. M.; Cook, H. W.; Ridgway, N. D., Effect of fumonisin B1 on phosphatidylethanolamine biosynthesis in Chinese hamster ovary cells. Biochim. Biophys. Acta, 1996, 1304 (3), 190-196.
71. Shimeno, H.; Soeda, S.; Sakamoto, M.; Kouchi, T.; Kowakame, T.; Kihara, T., Partial purification and characterization of sphingosine N-acyltransferase (ceramide synthase) from bovine liver mitochondrion-rich fraction. Lipids, 1998, 33 (6), 601-605.
72. Bionda, C.; Portoukalian, J.; Schmitt, D.; Rodriguez-Lafrasse, C.; Ardail, D., Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem. J., 2004, 382 (Pt 2), 527-533.
73. Beauchamp, E.; Tekpli, X.; Marteil, G.; Lagadic-Gossmann, D.; Legrand, P.; Rioux, V., N-Myristoylation targets dihydroceramide Delta4-desaturase 1 to mitochondria: partial involvement in the apoptotic effect of myristic acid. Biochimie, 2009, 91 (11-12), 1411-1419.
74. Michel, C.; van Echten-Deckert, G., Conversion of dihydro-ceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum. FEBS Lett., 1997, 416 (2), 153-155.
75. Hanada, K.; Kumagai, K.; Tomishige, N.; Kawano, M., CERT and intracellular trafficking of ceramide. Biochim. Biophys. Acta, 2007.
76. Futerman, A. H.; Stieger, B.; Hubbard, A. L.; Pagano, R. E., Sphingomyelin synthesis in rat liver occurs predominantly at the cis and medial cisternae of the Golgi apparatus. J. Biol. Chem., 1990, 265 (15), 8650-8657.
77. Halter, D.; Neumann, S.; van Dijk, S. M.; Wolthoorn, J.; de Maziere, A. M.; Vieira, O. V.; Mattjus, P.; Klumperman, J.; van Meer, G.; Sprong, H., Pre-and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J. Cell Biol., 2007, 179 (1), 101-115.
78. Lopez-Montero, I.; Rodriguez, N.; Cribier, S.; Pohl, A.; Velez, M.; Devaux, P. F., Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J. Biol. Chem, 2005, 280 (27), 25811-25819.
79. Mitsutake, S.; Igarashi, Y., Transbilayer movement of ceramide in the plasma membrane of live cells. Biochem. Biophys. Res. Commun., 2007, 359 (3), 622-627.
80. Futerman, A. H.; Pagano, R. E., Determination of the intracellular sites and topology of glucosylceramide synthesis in rat liver. Biochem. J., 1991, 280 (Pt 2), 295-302.
81. Coste, H.; Martel, M. B.; Got, R., Topology of glucosylceramide synthesis in Golgi membranes from porcine submaxillary glands. Biochim. Biophys. Acta, 1986, 858 (1), 6-12.
82. Jeckel, D.; Karrenbauer, A.; Burger, K. N.; van Meer, G.; Wieland, F., Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J. Cell Biol. 1992, 117 (2), 259-267.
83. Burger, K. N.; van der Bijl, P.; van Meer, G., Topology of sphingolipid galactosyltransferases in ER and Golgi: transbilayer movement of monohexosyl sphingolipids is required for higher glycosphingolipid biosynthesis. J. Cell Biol., 1996, 133 (1), 15-28.
84. Sprong, H.; Kruithof, B.; Leijendekker, R.; Slot, J. W.; van Meer, G.; van der Sluijs, P., UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. J. Biol. Chem., 1998, 273 (40), 25880-25888.
85. Buton, X.; Herve, P.; Kubelt, J.; Tannert, A.; Burger, K. N.; Fellmann, P.; Muller, P.; Herrmann, A.; Seigneuret, M.; Devaux, P. F., Transbilayer movement of monohexosylsphingolipids in endoplasmic reticulum and Golgi membranes. Biochemistry 2002, 41 (43), 13106-13115.
86. Kolzer, M.; Ferlinz, K.; Bartelsen, O.; Hoops, S. L.; Lang, F.; Sandhoff, K., Functional characterization of the postulated intramolecular sphingolipid activator protein domain of human acid sphingomyelinase. Biol. Chem., 2004, 385 (12), 1193-1195.
87. Tani, M.; Ito, M.; Igarashi, Y., Ceramide/sphingosine/sphingosine 1-phosphate metabolism on the cell surface and in the extracellular space. Cell Signal, 2007, 19 (2), 229-237.
88. Ancellin, N.; Colmont, C.; Su, J.; Li, Q.; Mittereder, N.; Chae, S. S.; Stefansson, S.; Liau, G.; Hla, T., Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J. Biol. Chem., 2002, 277 (8), 6667-6675.
89. Kim, R. H.; Takabe, K.; Milstien, S.; Spiegel, S., Export and functions of sphingosine-1-phosphate. Biochim. Biophys. Acta, 2009, 1791 (7), 692-696.
90. Taha, T. A.; Argraves, K. M.; Obeid, L. M., Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochim. Biophys. Acta, 2004, 1682 (1-3), 48-55.
91. Barenholz, Y.; Thompson, T. E., Sphingomyelins in bilayers and biological membranes. Biochim. Biophys. Acta, 1980, 604 (2), 129-158.
92. Linardic, C. M.; Hannun, Y. A., Identification of a distinct pool of sphingomyelin involved in the sphingomyelin cycle. J. Biol. Chem., 1994, 269 (38), 23530-23537.
93. Pettus, B. J.; Chalfant, C. E.; Hannun, Y. A., Ceramide in apoptosis: an overview and current perspectives. Biochim. Biophys. Acta, 2002, 1585 (2-3), 114-125.
94. Obeid, L. M.; Linardic, C. M.; Karolak, L. A.; Hannun, Y. A., Programmed cell death induced by ceramide. Science, 1993, 259 (5102), 1769-1771.
95. Bleicher, R. J.; Cabot, M. C., Glucosylceramide synthase and apoptosis. Biochim. Biophys. Acta, 2002, 1585 (2-3), 172-178.
96. Taha, T. A.; Kitatani, K.; El-Alwani, M.; Bielawski, J.; Hannun, Y. A.; Obeid, L. M., Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. Faseb J., 2006, 20 (3), 482-484.
97. Liu, Y. Y.; Han, T. Y.; Giuliano, A. E.; Cabot, M. C., Ceramide glycosylation potentiates cellular multidrug resistance. Faseb J., 2001, 15 (3), 719-730.
98. Olivera, A.; Kohama, T.; Edsall, L.; Nava, V.; Cuvillier, O.; Poulton, S.; Spiegel, S., Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J. Cell Biol., 1999, 147 (3), 545-558.
99. Edsall, L. C.; Cuvillier, O.; Twitty, S.; Spiegel, S.; Milstien, S., Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J. Neurochem., 2001, 76 (5), 1573-1584.
100. Okazaki, T.; Bell, R. M.; Hannun, Y. A., Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J. Biol. Chem., 1989, 264 (32), 19076-19080.
101. Kim, M. Y.; Linardic, C.; Obeid, L.; Hannun, Y., Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation. J. Biol. Chem., 1991, 266 (1), 484-489.
102. Cifone, M. G.; De Maria, R.; Roncaioli, P.; Rippo, M. R.; Azuma, M.; Lanier, L. L.; Santoni, A.; Testi, R., Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase. J. Exp. Med.,1994, 180 (4), 1547-1552.
103. Jayadev, S.; Liu, B.; Bielawska, A. E.; Lee, J. Y.; Nazaire, F.; Pushkareva, M.; Obeid, L. M.; Hannun, Y. A., Role for ceramide in cell cycle arrest. J. Biol. Chem., 1995, 270 (5), 2047-2052.
104. Clarke, C. J.; Hannun, Y. A., Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim. Biophys. Acta, 2006, 1758 (12), 1893-1901.
105. Devillard, R.; Galvani, S.; Thiers, J. C.; Guenet, J. L.; Hannun, Y.; Bielawski, J.; Negre-Salvayre, A.; Salvayre, R.; Auge, N., Stress-induced sphingolipid signaling: role of type-2 neutral sphingomyelinase in murine cell apoptosis and proliferation. PLoS One, 5 (3), e9826.
106. Krut, O.; Wiegmann, K.; Kashkar, H.; Yazdanpanah, B.; Kronke, M., Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein. J. Biol. Chem., 2006, 281 (19), 13784-13793.
107. Corcoran, C. A.; He, Q.; Ponnusamy, S.; Ogretmen, B.; Huang, Y.; Sheikh, M. S., Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Mol. Cancer Res., 2008, 6 (5), 795-807.
108. Wu, B. X.; Rajagopalan, V.; Roddy, P. L.; Clarke, C. J.; Hannun, Y. A., Identification and characterization of murine mitochondrial-associated neutral sphingomyelinase (ma-nsmase), the mammalian sphingomyelin phosphodiesterase 5. J. Biol. Chem.,
109. Grassme, H.; Riethmuller, J.; Gulbins, E., Biological aspects of ceramide-enriched membrane domains. Prog. Lipid Res., 2007, 46 (3-4), 161-170.
110. Corre, I.; Niaudet, C.; Paris, F., Plasma membrane signaling induced by ionizing radiation. Mutat. Res.,
111. Haimovitz-Friedman, A.; Kan, C. C.; Ehleiter, D.; Persaud, R. S.; McLoughlin, M.; Fuks, Z.; Kolesnick, R. N., Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp. Med., 1994, 180 (2), 525-535.
112. Zeidan, Y. H.; Wu, B. X.; Jenkins, R. W.; Obeid, L. M.; Hannun, Y. A., A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. Faseb J., 2008, 22 (1), 183-193.
113. Jenkins, R. W.; Clarke, C. J.; Canals, D.; Snider, A. J.; Gault, C. R.; Heffernan-Stroud, L.; Wu, B. X.; Simbari, F.; Roddy, P.; Kitatani, K.; Obeid, L. M.; Hannun, Y. A., Regulation of CC Ligand 5/RANTES by Acid Sphingomyelinase and Acid Ceramidase. The J. Biol. Chem., 2011, 286 (15), 13292-13303.
114. Perrotta, C.; Bizzozero, L.; Cazzato, D.; Morlacchi, S.; Assi, E.; Simbari, F.; Zhang, Y.; Gulbins, E.; Bassi, M. T.; Rosa, P.; Clementi, E., Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. The J. Biol. Chem., 2010, 285 (51), 40240-40251.
115. Santana, P.; Pena, L. A.; Haimovitz-Friedman, A.; Martin, S.; Green, D.; McLoughlin, M.; Cordon-Cardo, C.; Schuchman, E. H.; Fuks, Z.; Kolesnick, R., Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell, 1996, 86 (2), 189-199.
116. Paris, F.; Fuks, Z.; Kang, A.; Capodieci, P.; Juan, G.; Ehleiter, D.; Haimovitz-Friedman, A.; Cordon-Cardo, C.; Kolesnick, R., Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science, 2001, 293 (5528), 293-297.
117. Pena, L. A.; Fuks, Z.; Kolesnick, R. N., Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res., 2000, 60 (2), 321-327.
118. Garcia-Barros, M.; Paris, F.; Cordon-Cardo, C.; Lyden, D.; Rafii, S.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R., Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 2003, 300 (5622), 1155-1159.
119. Kirschnek, S.; Paris, F.; Weller, M.; Grassme, H.; Ferlinz, K.; Riehle, A.; Fuks, Z.; Kolesnick, R.; Gulbins, E., CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J. Biol. Chem., 2000, 275 (35), 27316-27323.
120. Garcia-Ruiz, C.; Colell, A.; Mari, M.; Morales, A.; Calvo, M.; Enrich, C.; Fernandez-Checa, J. C., Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J. Clin. Invest., 2003, 111 (2), 197-208.
121. Adam, D.; Wiegmann, K.; Adam-Klages, S.; Ruff, A.; Kronke, M., A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway. J. Biol. Chem., 1996, 271 (24), 14617-14622.
122. Brenner, B.; Ferlinz, K.; Grassme, H.; Weller, M.; Koppenhoefer, U.; Dichgans, J.; Sandhoff, K.; Lang, F.; Gulbins, E., Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Differ., 1998, 5 (1), 29-37.
123. Vit, J. P.; Rosselli, F., Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis. Oncogene, 2003, 22 (54), 8645-8652.
124. Bose, R.; Verheij, M.; Haimovitz-Friedman, A.; Scotto, K.; Fuks, Z.; Kolesnick, R., Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell, 1995, 82 (3), 405-414.
125. Shimabukuro, M.; Higa, M.; Zhou, Y. T.; Wang, M. Y.; Newgard, C. B.; Unger, R. H., Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J. Biol. Chem., 1998, 273 (49), 32487-32490.
126. Gomez del Pulgar, T.; Velasco, G.; Sanchez, C.; Haro, A.; Guzman, M., De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem. J., 2002, 363 (Pt 1), 183-188.
127. He, X.; Guan, X. L.; Ong, W. Y.; Farooqui, A. A.; Wenk, M. R., Expression, activity, and role of serine palmitoyltransferase in the rat hippocampus after kainate injury. J. Neurosci. Res., 2007, 85 (2), 423-432.
128. Perry, D. K.; Carton, J.; Shah, A. K.; Meredith, F.; Uhlinger, D. J.; Hannun, Y. A., Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem., 2000, 275 (12), 9078-9084.
129. Herget, T.; Esdar, C.; Oehrlein, S. A.; Heinrich, M.; Schutze, S.; Maelicke, A.; van Echten-Deckert, G., Production of ceramides causes apoptosis during early neural differentiation in vitro. J. Biol. Chem., 2000, 275 (39), 30344-30354.
130. Scarlatti, F.; Sala, G.; Somenzi, G.; Signorelli, P.; Sacchi, N.; Ghidoni, R., Resveratrol induces growth inhibition and apoptosis in metastatic breast cancer cells via de novo ceramide signaling. Faseb J., 2003, 17 (15), 2339-2341.
131. Granado, M. H.; Gangoiti, P.; Ouro, A.; Arana, L.; Gomez-Munoz, A., Ceramide 1-phosphate inhibits serine palmitoyltransferase and blocks apoptosis in alveolar macrophages. Biochim. Biophys. Acta, 2009, 1791 (4), 263-272.
132. Gable, K.; Slife, H.; Bacikova, D.; Monaghan, E.; Dunn, T. M., Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity. J. Biol. Chem., 2000, 275 (11), 7597-7603.
133. Han, G.; Gupta, S. D.; Gable, K.; Niranjanakumari, S.; Moitra, P.; Eichler, F.; Brown, R. H., Jr.; Harmon, J. M.; Dunn, T. M., Identification of small subunits of mammalian serine palmitoyl-transferase that confer distinct acyl-CoA substrate specificities. Proc. Natl. Acad. Sci. USA 2009, 106 (20), 8186-8191.
134. Bourteele, S.; Hausser, A.; Doppler, H.; Horn-Muller, J.; Ropke, C.; Schwarzmann, G.; Pfizenmaier, K.; Muller, G., Tumor necrosis factor induces ceramide oscillations and negatively controls sphingolipid synthases by caspases in apoptotic Kym-1 cells. J. Biol. Chem., 1998, 273 (47), 31245-31251.
135. Liao, W. C.; Haimovitz-Friedman, A.; Persaud, R. S.; McLoughlin, M.; Ehleiter, D.; Zhang, N.; Gatei, M.; Lavin, M.; Kolesnick, R.; Fuks, Z., Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. J. Biol. Chem., 1999, 274 (25), 17908-17917.
136. Garzotto, M.; White-Jones, M.; Jiang, Y.; Ehleiter, D.; Liao, W. C.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R., 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res., 1998, 58 (10), 2260-2264.
137. Garzotto, M.; Haimovitz-Friedman, A.; Liao, W. C.; White-Jones, M.; Huryk, R.; Heston, W. D.; Cardon-Cardo, C.; Kolesnick, R.; Fuks, Z., Reversal of radiation resistance in LNCaP cells by targeting apoptosis through ceramide synthase. Cancer Res., 1999, 59 (20), 5194-5201.
138. Truman, J. P.; Gueven, N.; Lavin, M.; Leibel, S.; Kolesnick, R.; Fuks, Z.; Haimovitz-Friedman, A., Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis. J. Biol. Chem., 2005, 280 (24), 23262-23272.
139. Truman, J. P.; Rotenberg, S. A.; Kang, J. H.; Lerman, G.; Fuks, Z.; Kolesnick, R.; Marquez, V. E.; Haimovitz-Friedman, A., PKCalpha activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo. Cancer Biol. Ther., 2009, 8 (1), 54-63.
140. Sridevi, P.; Alexander, H.; Laviad, E. L.; Pewzner-Jung, Y.; Hannink, M.; Futerman, A. H.; Alexander, S., Ceramide synthase 1 is regulated by proteasomal mediated turnover. Biochim. Biophys. Acta, 2009, 1793 (7), 1218-1227.
141. Gustafsson, K.; Sander, B.; Bielawski, J.; Hannun, Y. A.; Flygare, J., Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism. Mol. Cancer Res., 2009, 7 (7), 1086-1098.
142. Jin, J.; Mullen, T. D.; Hou, Q.; Bielawski, J.; Bielawska, A.; Zhang, X.; Obeid, L. M.; Hannun, Y. A.; Hsu, Y. T., AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells. J. Lipid Res., 2009, 50 (12), 2389-2397.
143. Panjarian, S.; Kozhaya, L.; Arayssi, S.; Yehia, M.; Bielawski, J.; Bielawska, A.; Usta, J.; Hannun, Y. A.; Obeid, L. M.; Dbaibo, G. S., De novo N-palmitoylsphingosine synthesis is the major biochemical mechanism of ceramide accumulation following p53 up-regulation. Prostaglandins Other Lipid Mediat., 2008, 86 (1-4), 41-48.
144. Kitatani, K.; Idkowiak-Baldys, J.; Hannun, Y. A., The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal., 2008, 20 (6), 1010-1018.
145. Cuvillier, O.; Nava, V. E.; Murthy, S. K.; Edsall, L. C.; Levade, T.; Milstien, S.; Spiegel, S., Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ., 2001, 8 (2), 162-171.
146. Takeda, S.; Mitsutake, S.; Tsuji, K.; Igarashi, Y., Apoptosis occurs via the ceramide recycling pathway in human HaCaT keratinocytes. J. Biochem. (Tokyo), 2006, 139 (2), 255-262.
147. Jin, J.; Hou, Q.; Mullen, T. D.; Zeidan, Y. H.; Bielawski, J.; Kraveka, J. M.; Bielawska, A.; Obeid, L. M.; Hannun, Y. A.; Hsu, Y. T., Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells. J. Biol. Chem., 2008, 283 (39), 26509-26517.
148. Adam-Klages, S.; Adam, D.; Wiegmann, K.; Struve, S.; Kolanus, W.; Schneider-Mergener, J.; Kronke, M., FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell, 1996, 86 (6), 937-947.
149. Segui, B.; Cuvillier, O.; Adam-Klages, S.; Garcia, V.; Malagarie-Cazenave, S.; Leveque, S.; Caspar-Bauguil, S.; Coudert, J.; Salvayre, R.; Kronke, M.; Levade, T., Involvement of FAN in TNF-induced apoptosis. J. Clin. Invest., 2001, 108 (1), 143-151.
150. Schwandner, R.; Wiegmann, K.; Bernardo, K.; Kreder, D.; Kronke, M., TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J. Biol. Chem., 1998, 273 (10), 5916-5922.
151. Rotolo, J. A.; Zhang, J.; Donepudi, M.; Lee, H.; Fuks, Z.; Kolesnick, R., Caspase-dependent and -independent activation of acid sphingomyelinase signaling. J. Biol. Chem., 2005, 280 (28), 26425-26434.
152. Grassme, H.; Cremesti, A.; Kolesnick, R.; Gulbins, E., Ceramidemediated clustering is required for CD95-DISC formation. Oncogene, 2003, 22 (35), 5457-5470.
153. Dbaibo, G. S.; Pushkareva, M. Y.; Rachid, R. A.; Alter, N.; Smyth, M. J.; Obeid, L. M.; Hannun, Y. A., P53-dependent ceramide response to genotoxic stress. J, Clin, Invest., 1998, 102 (2), 329-339.
154. Sawada, M.; Nakashima, S.; Kiyono, T.; Nakagawa, M.; Yamada, J.; Yamakawa, H.; Banno, Y.; Shinoda, J.; Nishimura, Y.; Nozawa, Y.; Sakai, N., P53 regulates ceramide formation by neutral sphingomyelinase through reactive oxygen species in human glioma cells. Oncogene, 2001, 20 (11), 1368-1378.
155. Hara, S.; Nakashima, S.; Kiyono, T.; Sawada, M.; Yoshimura, S.; Iwama, T.; Banno, Y.; Shinoda, J.; Sakai, N., p53-Independent ceramide formation in human glioma cells during gammaradiation-induced apoptosis. Cell Death Differ., 2004, 11 (8), 853-861.
156. Ch'ang, H. J.; Maj, J. G.; Paris, F.; Xing, H. R.; Zhang, J.; Truman, J. P.; Cardon-Cardo, C.; Haimovitz-Friedman, A.; Kolesnick, R.; Fuks, Z., ATM regulates target switching to escalating doses of radiation in the intestines. Nat. Med., 2005, 11 (5), 484-490.
157. Rotolo, J. A.; Mesicek, J.; Maj, J.; Truman, J. P.; Haimovitz-Friedman, A.; Kolesnick, R.; Fuks, Z., Regulation of ceramide synthase-mediated crypt epithelium apoptosis by DNA damage repair enzymes. Cancer Res., 70 (3), 957-967.
158. Zhang, J.; Alter, N.; Reed, J. C.; Borner, C.; Obeid, L. M.; Hannun, Y. A., Bcl-2 interrupts the ceramide-mediated pathway of cell death. Proc. Natl. Acad. Sci. USA, 1996, 93 (11), 5325-5328.
159. Wiesner, D. A.; Kilkus, J. P.; Gottschalk, A. R.; Quintans, J.; Dawson, G., 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 (15), 9868-9876.
160. Liu, B.; Andrieu-Abadie, N.; Levade, T.; Zhang, P.; Obeid, L. M.; Hannun, Y. A., Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J. Biol. Chem., 1998, 273 (18), 11313-11320.
161. El-Assaad, W.; El-Sabban, M.; Awaraji, C.; Abboushi, N.; Dbaibo, G. S., Distinct sites of action of Bcl-2 and Bcl-xL in the ceramide pathway of apoptosis. Biochem. J., 1998, 336 (Pt 3), 735-741.
162. Okamoto, Y.; Obeid, L. M.; Hannun, Y. A., Bcl-xL interrupts oxidative activation of neutral sphingomyelinase. FEBS Lett., 2002, 530 (1-3), 104-108.
163. Tepper, A. D.; de Vries, E.; van Blitterswijk, W. J.; Borst, J., Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95-and DNA damage-induced apoptosis. J. Clin. Invest., 1999, 103 (7), 971-978.
164. El-Assaad, W.; Kozhaya, L.; Araysi, S.; Panjarian, S.; Bitar, F. F.; Baz, E.; El-Sabban, M. E.; Dbaibo, G. S., Ceramide and glutathione define two independently regulated pathways of cell death initiated by p53 in Molt-4 leukaemia cells. Biochem. J., 2003, 376 (Pt 3), 725-732.
165. Sawada, M.; Nakashima, S.; Banno, Y.; Yamakawa, H.; Takenaka, K.; Shinoda, J.; Nishimura, Y.; Sakai, N.; Nozawa, Y., Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells. Oncogene, 2000, 19 (31), 3508-3520.
166. Kawatani, M.; Uchi, M.; Simizu, S.; Osada, H.; Imoto, M., Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamycin-induced apoptosis. Exp. Cell Res., 2003, 286 (1), 57-66.
167. Siskind, L. J.; Mullen, T. D.; Rosales, K. R.; Clarke, C. J.; Hernandez-Corbacho, M. J.; Edinger, A. L.; Obeid, L. M., The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J. Biol. Chem.
168. Gamen, S.; Marzo, I.; Anel, A.; Pineiro, A.; Naval, J., CPP32 inhibition prevents Fas-induced ceramide generation and apoptosis in human cells. FEBS Lett., 1996, 390 (2), 232-237.
169. Tepper, A. D.; Cock, J. G.; de Vries, E.; Borst, J.; van Blitterswijk, W. J., CD95/Fas-induced ceramide formation proceeds with slow kinetics and is not blocked by caspase-3/CPP32 inhibition. J. Biol. Chem., 1997, 272 (39), 24308-24312.
170. Monney, L.; Olivier, R.; Otter, I.; Jansen, B.; Poirier, G. G.; Borner, C., 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 (1-2), 295-303.
171. Chen, L.; Kim, T. J.; Pillai, S., Inhibition of caspase activity prevents anti-IgM induced apoptosis but not ceramide generation in WEHI 231 B cells. Mol. Immunol., 1998, 35 (4), 195-205.
172. Sawada, M.; Nakashima, S.; Banno, Y.; Yamakawa, H.; Hayashi, K.; Takenaka, K.; Nishimura, Y.; Sakai, N.; Nozawa, Y., Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ., 2000, 7 (9), 761-772.
173. Sumitomo, M.; Ohba, M.; Asakuma, J.; Asano, T.; Kuroki, T.; Hayakawa, M., Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J. Clin. Invest., 2002, 109 (6), 827-836.
174. Erdreich-Epstein, A.; Tran, L. B.; Bowman, N. N.; Wang, H.; Cabot, M. C.; Durden, D. L.; Vlckova, J.; Reynolds, C. P.; Stins, M. F.; Groshen, S.; Millard, M., Ceramide signaling in fenretinide-induced endothelial cell apoptosis. J. Biol. Chem.,2002, 277 (51), 49531-49537.
175. Rehman, F.; Shanmugasundaram, P.; Schrey, M. P., Fenretinide stimulates redox-sensitive ceramide production in breast cancer cells: potential role in drug-induced cytotoxicity. Br. J. Cancer, 2004, 91 (10), 1821-1828.
176. Kraveka, J. M.; Li, L.; Szulc, Z. M.; Bielawski, J.; Ogretmen, B.; Hannun, Y. A.; Obeid, L. M.; Bielawska, A., Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem., 2007, 282 (23), 16718-16728.
177. Conus, S.; Simon, H. U., Cathepsins: key modulators of cell death and inflammatory responses. Biochem. Pharmacol., 2008, 76 (11), 1374-1382.
178. Harwood, S. M.; Yaqoob, M. M.; Allen, D. A., Caspase and calpain function in cell death: bridging the gap between apoptosis and necrosis. Ann. Clin. Biochem., 2005, 42 (Pt 6), 415-431.
179. Taha, T. A.; Osta, W.; Kozhaya, L.; Bielawski, J.; Johnson, K. R.; Gillanders, W. E.; Dbaibo, G. S.; Hannun, Y. A.; Obeid, L. M., Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J. Biol. Chem., 2004, 279 (19), 20546-20554.
180. Becker, K. P.; Hannun, Y. A., Protein kinase C and phospholipase D: intimate interactions in intracellular signaling. Cell Mol. Life Sci., 2005, 62 (13), 1448-1461.
181. Charruyer, A.; Jean, C.; Colomba, A.; Jaffrezou, J. P.; Quillet-Mary, A.; Laurent, G.; Bezombes, C., PKCzeta protects against UV-C-induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production. Biochem. J., 2007, 405 (1), 77-83.
182. Clarke, C. J.; Guthrie, J. M.; Hannun, Y. A., Regulation of neutral sphingomyelinase-2 (nSMase2) by tumor necrosis factor-alpha involves protein kinase C-delta in lung epithelial cells. Mol. Pharmacol., 2008, 74 (4), 1022-1032.
183. Hannun, Y. A.; Loomis, C. R.; Merrill, A. H., Jr.; Bell, R. M., Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J. Biol. Chem., 1986, 261 (27), 12604-12609.
184. Merrill, A. H., Jr.; Sereni, A. M.; Stevens, V. L.; Hannun, Y. A.; Bell, R. M.; Kinkade, J. M., Jr., Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases. J. Biol. Chem., 1986, 261 (27), 12610-12615.
185. Kawatani, M.; Simizu, S.; Osada, H.; Takada, M.; Arber, N.; Imoto, M., Involvement of protein kinase C-regulated ceramide generation in inostamycin-induced apoptosis. Exp. Cell Res., 2000, 259 (2), 389-397.
186. Kitatani, K.; Sheldon, K.; Anelli, V.; Jenkins, R. W.; Sun, Y.; Grabowski, G. A.; Obeid, L. M.; Hannun, Y. A., Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid. J. Biol. Chem., 2009, 284 (19), 12979-12988.
187. Sawai, H.; Okazaki, T.; Takeda, Y.; Tashima, M.; Sawada, H.; Okuma, M.; Kishi, S.; Umehara, H.; Domae, N., Ceramide-induced translocation of protein kinase C-delta and -epsilon to the cytosol. Implications in apoptosis. J. Biol. Chem., 1997, 272 (4), 2452-2458.
188. Huwiler, A.; Fabbro, D.; Pfeilschifter, J., Selective ceramide binding to protein kinase C-alpha and -delta isoenzymes in renal mesangial cells. Biochemistry, 1998, 37 (41), 14556-14562.
189. Kajimoto, T.; Ohmori, S.; Shirai, Y.; Sakai, N.; Saito, N., Subtype-specific translocation of the delta subtype of protein kinase C and its activation by tyrosine phosphorylation induced by ceramide in HeLa cells. Mol. Cell Biol., 2001, 21 (5), 1769-1783.
190. Kajimoto, T.; Shirai, Y.; Sakai, N.; Yamamoto, T.; Matsuzaki, H.; Kikkawa, U.; Saito, N., Ceramide-induced apoptosis by translocation, phosphorylation, and activation of protein kinase Cdelta in the Golgi complex. J. Biol. Chem., 2004, 279 (13), 12668-12676.
191. Dhanasekaran, D. N.; Reddy, E. P., JNK signaling in apoptosis. Oncogene, 2008, 27 (48), 6245-6251.
192. Yu, J.; Novgorodov, S. A.; Chudakova, D.; Zhu, H.; Bielawska, A.; Bielawski, J.; Obeid, L. M.; Kindy, M. S.; Gudz, T. I., JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J. Biol. Chem., 2007, 282 (35), 25940-25949.
193. Moussavi, M.; Assi, K.; Gomez-Munoz, A.; Salh, B., Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis, 2006, 27 (8), 1636-1644.
194. Gustafsson, K.; Christensson, B.; Sander, B.; Flygare, J., Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol. Pharmacol., 2006, 70 (5), 1612-1620.
195. Herrera, B.; Carracedo, A.; Diez-Zaera, M.; Gomez del Pulgar, T.; Guzman, M.; Velasco, G., The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp. Cell Res., 2006, 312 (11), 2121-2131.
196. Kroesen, B. J.; Pettus, B.; Luberto, C.; Busman, M.; Sietsma, H.; de Leij, L.; Hannun, Y. A., Induction of apoptosis through B-cell receptor cross-linking occurs via de novo generated C16-ceramide and involves mitochondria. J. Biol. Chem., 2001, 276 (17), 13606-13614.
197. Jiang, Q.; Wong, J.; Fyrst, H.; Saba, J. D.; Ames, B. N., gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc. Natl. Acad. Sci., USA 2004, 101 (51), 17825-17830.
198. Dai, Q.; Liu, J.; Chen, J.; Durrant, D.; McIntyre, T. M.; Lee, R. M., Mitochondrial ceramide increases in UV-irradiated HeLa cells and is mainly derived from hydrolysis of sphingomyelin. Oncogene, 2004, 23 (20), 3650-3658.
199. Colombini, M., Ceramide channels and their role in mitochondria-mediated apoptosis. Biochim. Biophys. Acta
200. Siskind, L. J.; Colombini, M., The lipids C2-and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem., 2000, 275 (49), 38640-38644.
201. Siskind, L. J.; Kolesnick, R. N.; Colombini, M., Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J. Biol. Chem., 2002, 277 (30), 26796-26803.
202. Siskind, L. J.; Kolesnick, R. N.; Colombini, M., Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion, 2006, 6 (3), 118-125.
203. Samanta, S.; Stiban, J.; Maugel, T. K.; Colombini, M., Visualization of ceramide channels by transmission electron microscopy. Biochimica. et Biophysica. Acta, 2011, 1808 (4), 1196-1201.
204. Siskind, L. J.; Feinstein, L.; Yu, T.; Davis, J. S.; Jones, D.; Choi, J.; Zuckerman, J. E.; Tan, W.; Hill, R. B.; Hardwick, J. M.; Colombini, M., Anti-apoptotic Bcl-2 Family Proteins Disassemble Ceramide Channels. J. Biol. Chem., 2008, 283 (11), 6622-6630.
205. Ganesan, V.; Perera, M. N.; Colombini, D.; Datskovskiy, D.; Chadha, K.; Colombini, M., Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane. Apoptosis, 15 (5), 553-562.
206. Novgorodov, S. A.; Gudz, T. I.; Obeid, L. M., Long-chain ceramide is a potent inhibitor of the mitochondrial permeability transition pore. J. Biol. Chem., 2008, 283 (36), 24707-24717.
207. Rath, G.; Schneider, C.; Langlois, B.; Sartelet, H.; Morjani, H.; Btaouri, H. E.; Dedieu, S.; Martiny, L., De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int. J. Biochem. Cell Biol., 2009, 41 (5), 1165-1172.
208. Seumois, G.; Fillet, M.; Gillet, L.; Faccinetto, C.; Desmet, C.; Francois, C.; Dewals, B.; Oury, C.; Vanderplasschen, A.; Lekeux, P.; Bureau, F., De novo C16-and C24-ceramide generation contributes to spontaneous neutrophil apoptosis. J. Leukoc. Biol., 2007, 81 (6), 1477-1486.
209. Medler, T. R.; Petrusca, D. N.; Lee, P. J.; Hubbard, W. C.; Berdyshev, E. V.; Skirball, J.; Kamocki, K.; Schuchman, E.; Tuder, R. M.; Petrache, I., Apoptotic sphingolipid signaling by ceramides in lung endothelial cells. Am. J. Respir. Cell Mol. Biol., 2008, 38 (6), 639-646.
210. Kroesen, B. J.; Jacobs, S.; Pettus, B. J.; Sietsma, H.; Kok, J. W.; Hannun, Y. A.; de Leij, L. F., BcR-induced apoptosis involves differential regulation of C16 and C24-ceramide formation and sphingolipid-dependent activation of the proteasome. J. Biol. Chem., 2003, 278 (17), 14723-14731.
211. Wispriyono, B.; Schmelz, E.; Pelayo, H.; Hanada, K.; Separovic, D., A role for the de novo sphingolipids in apoptosis of photosensitized cells. Exp. Cell Res., 2002, 279 (1), 153-165.
212. Ruvolo, P. P., Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol. Res., 2003, 47 (5), 383-392.
213. Dobrowsky, R. T.; Hannun, Y. A., Ceramide stimulates a cytosolic protein phosphatase. J. Biol. Chem.,1992, 267 (8), 5048-5051.
214. Dobrowsky, R. T.; Kamibayashi, C.; Mumby, M. C.; Hannun, Y. A., Ceramide activates heterotrimeric protein phosphatase 2A. J. Biol. Chem., 1993, 268 (21), 15523-15530.
215. Chalfant, C. E.; Kishikawa, K.; Mumby, M. C.; Kamibayashi, C.; Bielawska, A.; Hannun, Y. A., Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem., 1999, 274 (29), 20313-20317.
216. Carracedo, A.; Geelen, M. J.; Diez, M.; Hanada, K.; Guzman, M.; Velasco, G., Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids. Biochem. J., 2004, 380 (Pt 2), 435-440.
217. Willaime, S.; Vanhoutte, P.; Caboche, J.; Lemaigre-Dubreuil, Y.; Mariani, J.; Brugg, B., 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., 2001, 13 (11), 2037-2046.
218. Tavarini, S.; Colombaioni, L.; Garcia-Gil, M., Sphingomyelinase metabolites control survival and apoptotic death in SH-SY5Y neuroblastoma cells. Neurosci. Lett., 2000, 285 (3), 185-188.
219. Hida, H.; Nagano, S.; Takeda, M.; Soliven, B., Regulation of mitogen-activated protein kinases by sphingolipid products in oligodendrocytes. J. Neurosci., 1999, 19 (17), 7458-7467.
220. Blazquez, C.; Galve-Roperh, I.; Guzman, M., De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. Faseb J., 2000, 14 (14), 2315-2322.
221. Kitatani, K.; Idkowiak-Baldys, J.; Bielawski, J.; Taha, T. A.; Jenkins, R. W.; Senkal, C. E.; Ogretmen, B.; Obeid, L. M.; Hannun, Y. A., Protein kinase C-induced activation of a ceramide/protein phosphatase 1 pathway leading to dephosphorylation of p38 MAPK. J. Biol. Chem., 2006, 281 (48), 36793-36802.
222. Carracedo, A.; Lorente, M.; Egia, A.; Blazquez, C.; Garcia, S.; Giroux, V.; Malicet, C.; Villuendas, R.; Gironella, M.; Gonzalez-Feria, L.; Piris, M. A.; Iovanna, J. L.; Guzman, M.; Velasco, G., The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell, 2006, 9 (4), 301-312.
223. Salazar, M.; Carracedo, A.; Salanueva, I. J.; Hernandez-Tiedra, S.; Lorente, M.; Egia, A.; Vazquez, P.; Blazquez, C.; Torres, S.; Garcia, S.; Nowak, J.; Fimia, G. M.; Piacentini, M.; Cecconi, F.; Pandolfi, P. P.; Gonzalez-Feria, L.; Iovanna, J. L.; Guzman, M.; Boya, P.; Velasco, G., Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J. Clin. Invest., 2009, 119 (5), 1359-1372.
224. Spassieva, S. D.; Mullen, T. D.; Townsend, D. M.; Obeid, L. M., Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem. J., 2009, 424 (2), 273-283.
225. Senkal, C. E.; Ponnusamy, S.; Bielawski, J.; Hannun, Y. A.; Ogretmen, B., Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J., 2010, 24 (1), 296-308.
226. Mullen, T. D.; Spassieva, S.; Jenkins, R. W.; Kitatani, K.; Bielawski, J.; Hannun, Y. A.; Obeid, L. M., Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J. Lipid Res., 2011, 52 (1), 68-77.
227. Senkal, C. E.; Ponnusamy, S.; Rossi, M. J.; Bialewski, J.; Sinha, D.; Jiang, J. C.; Jazwinski, S. M.; Hannun, Y. A.; Ogretmen, B., Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol. Cancer Ther., 2007, 6 (2), 712-722.
228. Baran, Y.; Salas, A.; Senkal, C. E.; Gunduz, U.; Bielawski, J.; Obeid, L. M.; Ogretmen, B., Alterations of ceramide/sphingosine-1-phosphate rheostat involve in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia (CML) cells. J. Biol. Chem., 2007.
229. Min, J.; Mesika, A.; Sivaguru, M.; Van Veldhoven, P. P.; Alexander, H.; Futerman, A. H.; Alexander, S., (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol. Cancer Res., 2007, 5 (8), 801-812.
230. Thorburn, A.; Behbakht, K.; Ford, H., TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them. Drug Resist. Updat., 2008, 11 (1-2), 17-24.
231. White-Gilbertson, S.; Mullen, T.; Senkal, C.; Lu, P.; Ogretmen, B.; Obeid, L.; Voelkel-Johnson, C., Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene, 2009.
232. Walker, T.; Mitchell, C.; Park, M. A.; Yacoub, A.; Graf, M.; Rahmani, M.; Houghton, P. J.; Voelkel-Johnson, C.; Grant, S.; Dent, P., Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. Mol. Pharmacol., 2009, 76 (2), 342-355.
233. Lebedeva, I. V.; Emdad, L.; Su, Z. Z.; Gupta, P.; Sauane, M.; Sarkar, D.; Staudt, M. R.; Liu, S. J.; Taher, M. M.; Xiao, R.; Barral, P.; Lee, S. G.; Wang, D.; Vozhilla, N.; Park, E. S.; Chatman, L.; Boukerche, H.; Ramesh, R.; Inoue, S.; Chada, S.; Li, R.; De Pass, A. L.; Mahasreshti, P. J.; Dmitriev, I. P.; Curiel, D. T.; Yacoub, A.; Grant, S.; Dent, P.; Senzer, N.; Nemunaitis, J. J.; Fisher, P. B., mda-7/IL-24, novel anticancer cytokine: focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review). Int. J. Oncol., 2007, 31 (5), 985-1007.
234. Cuzzocrea, S.; Di Paola, R.; Genovese, T.; Mazzon, E.; Esposito, E.; Crisafulli, C.; Bramanti, P.; Salvemini, D., Anti-inflammatory and anti-apoptotic effects of fumonisin B1, an inhibitor of ceramide synthase, in a rodent model of splanchnic ischemia and reperfusion injury. J. Pharmacol. Exp. Ther., 2008, 327 (1), 45-57.
235. Cuzzocrea, S.; Genovese, T.; Mazzon, E.; Esposito, E.; Crisafulli, C.; Di Paola, R.; Bramanti, P.; Salvemini, D., Fumonisin b1 reduces the development of multiple organ failure induced by zymosan in mice. Shock, 2009, 31 (2), 170-177.
236. Itoh, Y.; Yano, T.; Sendo, T.; Sueyasu, M.; Hirano, K.; Kanaide, H.; Oishi, R., Involvement of de novo ceramide synthesis in radiocontrast-induced renal tubular cell injury. Kidney Int., 2006, 69 (2), 288-297.
237. Benes, P.; Vetvicka, V.; Fusek, M., Cathepsin D--many functions of one aspartic protease. Crit. Rev. Oncol. Hematol., 2008, 68 (1), 12-28.
238. Heinrich, M.; Wickel, M.; Schneider-Brachert, W.; Sandberg, C.; Gahr, J.; Schwandner, R.; Weber, T.; Saftig, P.; Peters, C.; Brunner, J.; Kronke, M.; Schutze, S., Cathepsin D targeted by acid sphingomyelinase-derived ceramide. Embo J., 1999, 18 (19), 5252-5263.
239. Heinrich, M.; Neumeyer, J.; Jakob, M.; Hallas, C.; Tchikov, V.; Winoto-Morbach, S.; Wickel, M.; Schneider-Brachert, W.; Trauzold, A.; Hethke, A.; Schutze, S., Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ., 2004, 11 (5), 550-563.
240. Dumitru, C. A.; Sandalcioglu, I. E.; Wagner, M.; Weller, M.; Gulbins, E., Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. J. Mol. Med., 2009, 87 (11), 1123-1132.
241. Junttila, M. R.; Li, S. P.; Westermarck, J., Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. Faseb J., 2008, 22 (4), 954-965.
242. Kutuk, O.; Letai, A., Regulation of Bcl-2 family proteins by posttranslational modifications. Curr. Mol. Med., 2008, 8 (2), 102-118.
243. Chalfant, C. E.; Rathman, K.; Pinkerman, R. L.; Wood, R. E.; Obeid, L. M.; Ogretmen, B.; Hannun, Y. A., De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J. Biol. Chem., 2002, 277 (15), 12587-12595.
244. Chalfant, C. E.; Ogretmen, B.; Galadari, S.; Kroesen, B. J.; Pettus, B. J.; Hannun, Y. A., FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1. J. Biol. Chem., 2001, 276 (48), 44848-44855.
245. Ruvolo, P. P.; Deng, X.; Ito, T.; Carr, B. K.; May, W. S., Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J. Biol. Chem.,1999, 274 (29), 20296-20300.
246. Ruvolo, P. P.; Clark, W.; Mumby, M.; Gao, F.; May, W. S., A functional role for the B56 alpha-subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J. Biol. Chem., 2002, 277 (25), 22847-22852.
247. Xin, M.; Deng, X., Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. J. Biol. Chem., 2006, 281 (27), 18859-18867.
248. Lozano, J.; Berra, E.; Municio, M. M.; Diaz-Meco, M. T.; Dominguez, I.; Sanz, L.; Moscat, J., Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J. Biol. Chem., 1994, 269 (30), 19200-19202.
249. Muller, G.; Ayoub, M.; Storz, P.; Rennecke, J.; Fabbro, D.; Pfizenmaier, K., PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. Embo J., 1995, 14 (9), 1961-1969.
250. Bourbon, N. A.; Yun, J.; Kester, M., Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J. Biol. Chem., 2000, 275 (45), 35617-35623.
251. 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 (3), 271-274.
252. Bourbon, N. A.; Sandirasegarane, L.; Kester, M., Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J. Biol. Chem., 2002, 277 (5), 3286-3292.
253. Xin, M.; Gao, F.; May, W. S.; Flagg, T.; Deng, X., Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. J. Biol. Chem., 2007, 282 (29), 21268-21277.
254. Zhang, Y.; Yao, B.; Delikat, S.; Bayoumy, S.; Lin, X. H.; Basu, S.; McGinley, M.; Chan-Hui, P. Y.; Lichenstein, H.; Kolesnick, R., Kinase suppressor of Ras is ceramide-activated protein kinase. Cell, 1997, 89 (1), 63-72.
255. Michaud, N. R.; Therrien, M.; Cacace, A.; Edsall, L. C.; Spiegel, S.; Rubin, G. M.; Morrison, D. K., KSR stimulates Raf-1 activity in a kinase-independent manner. Proc. Natl. Acad. Sci. USA, 1997, 94 (24), 12792-12796.
256. Brown, M. D.; Sacks, D. B., Protein scaffolds in MAP kinase signalling. Cell Signal, 2009, 21 (4), 462-469.
257. Zafrullah, M.; Yin, X.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R., Kinase suppressor of Ras transphosphorylates c-Raf-1. Biochem. Biophys. Res. Commun., 2009, 390 (3), 434-40.
258. Basu, S.; Bayoumy, S.; Zhang, Y.; Lozano, J.; Kolesnick, R., BAD enables ceramide to signal apoptosis via Ras and Raf-1. J. Biol. Chem., 1998, 273 (46), 30419-30426.
259. Yin, X.; Zafrullah, M.; Lee, H.; Haimovitz-Friedman, A.; Fuks, Z.; Kolesnick, R., A ceramide-binding C1 domain mediates kinase suppressor of ras membrane translocation. Cell Physiol. Biochem., 2009, 24 (3-4), 219-230.
260. Venkataraman, K.; Riebeling, C.; Bodennec, J.; Riezman, H.; Allegood, J. C.; Sullards, M. C.; Merrill, A. H., Jr.; Futerman, A. H., Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J. Biol. Chem., 2002, 277 (38), 35642-35649.
261. Mizutani, Y.; Kihara, A.; Igarashi, Y., Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem. J., 2005, 390 (Pt 1), 263-271.
262. Spassieva, S.; Seo, J. G.; Jiang, J. C.; Bielawski, J.; Alvarez-Vasquez, F.; Jazwinski, S. M.; Hannun, Y. A.; Obeid, L. M., Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity. J. Biol. Chem., 2006, 281 (45), 33931-33938.
263. Guillas, I.; Jiang, J. C.; Vionnet, C.; Roubaty, C.; Uldry, D.; Chuard, R.; Wang, J.; Jazwinski, S. M.; Conzelmann, A., Human homologues of LAG1 reconstitute Acyl-CoA-dependent ceramide synthesis in yeast. J. Biol. Chem., 2003, 278 (39), 37083-37091.
264. Laviad, E. L.; Albee, L.; Pankova-Kholmyansky, I.; Epstein, S.; Park, H.; Merrill, A. H., Jr.; Futerman, A. H., Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J. Biol. Chem., 2008, 283 (9), 5677-5684.
265. Mizutani, Y.; Kihara, A.; Igarashi, Y., LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem. J., 2006, 398 (3), 531-538.
266. Riebeling, C.; Allegood, J. C.; Wang, E.; Merrill, A. H., Jr.; Futerman, A. H., Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J. Biol. Chem., 2003, 278 (44), 43452-43459.
267. Lahiri, S.; Futerman, A. H., LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl CoA as acyl donor. J. Biol. Chem., 2005.
268. Marchesini, N.; Hannun, Y. A., Acid and neutral sphin-gomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol., 2004, 82 (1), 27-44.
269. Tomiuk, S.; Hofmann, K.; Nix, M.; Zumbansen, M.; Stoffel, W., Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc. Natl. Acad. Sci. USA 1998, 95 (7), 3638-3643.