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The FASEB Journal, Vol 10, 1388-1397, Copyright © 1996 by The Federation of American Societies for Experimental Biology

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Sphingolipid metabolism and cell growth regulation

S Spiegel and AH Merrill Jr
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007, USA.

Sphingolipids have been implicated in the regulation of cell growth, differentiation, and programmed cell death. The current paradigm for their action is that complex sphingolipids such as gangliosides interact with growth factor receptors, the extracellular matrix, and neighboring cells, whereas the backbones--sphingosine and other long- chain or "sphingoid" bases, ceramides, and sphingosine 1-phosphate-- activate or inhibit protein kinases and phosphatases, ion transporters, and other regulatory machinery. Tumor necrosis factor-alpha, interleukin 1beta, and nerve growth factor, for example, induce sphingomyelin hydrolysis to ceramide. Other agonists, such as platelet- derived growth factor, trigger further hydrolysis of ceramide to sphingosine and activate sphingosine kinase to form sphingosine 1- phosphate. These metabolites either stimulate or inhibit growth and may be cytotoxic (in some cases via induction of apoptosis), depending on which products are formed (or added exogenously), the cellular levels (and possibly intracellular localization), and the cell type. In Swiss 3T3 cells, for example, sphingosine and sphingosine 1-phosphate are growth stimulatory at low concentrations via calcium mobilization from intracellular stores and activation of the mitogen-activated protein kinase (MAP kinase) pathway and transcription factors (AP-1), but are toxic at high concentrations. High levels of endogenous sphingoid bases are also produced by inhibition of ceramide synthase by fumonisins, mycotoxins produced by Fusarium moniliforme, resulting in growth stimulation or toxicity. Thus, sphingolipid metabolites appear to serve as second messengers for growth factors, cytokines, and other "physiological" agonists and, when elevated abnormally, to lead to disease.


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E. M. Schmelz, P. C. Roberts, E. M. Kustin, L. A. Lemonnier, M. C. Sullards, D. L. Dillehay, and A. H. Merrill Jr.
Modulation of Intracellular {beta}-Catenin Localization and Intestinal Tumorigenesis in Vivo and in Vitro by Sphingolipids
Cancer Res., September 1, 2001; 61(18): 6723 - 6729.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
A. Senchenkov, D. A. Litvak, and M. C. Cabot
Targeting Ceramide Metabolism--a Strategy for Overcoming Drug Resistance
J Natl Cancer Inst, March 7, 2001; 93(5): 347 - 357.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
R. MISASI, M. SORICE, L. DI MARZIO, W. M. CAMPANA, S. MOLINARI, M. G. CIFONE, A. PAVAN, G. M. PONTIERI, and J. S. O'BRIEN
Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase
FASEB J, February 1, 2001; 15(2): 467 - 474.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
G. P. v. N. Amerongen, M. A. Vermeer, and V. W. M. van Hinsbergh
Role of RhoA and Rho Kinase in Lysophosphatidic Acid-Induced Endothelial Barrier Dysfunction
Arterioscler Thromb Vasc Biol, December 1, 2000; 20 (12): e127 - e133.
[Abstract] [Full Text] [PDF]

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 BloodHome page
Y. Yatomi, T. Ohmori, G. Rile, F. Kazama, H. Okamoto, T. Sano, K. Satoh, S. Kume, G. Tigyi, Y. Igarashi, et al.
Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells
Blood, November 15, 2000; 96(10): 3431 - 3438.
[Abstract] [Full Text] [PDF]

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 Alcohol AlcoholHome page
J.-J. Liu, J.-Y. Wang, E. Hertervig, Y. Cheng, A. Nilsson, and R.-D. Duan
ACTIVATION OF NEUTRAL SPHINGOMYELINASE PARTICIPATES IN ETHANOL-INDUCED APOPTOSIS IN HEP G2 CELLS
Alcohol Alcohol., November 1, 2000; 35(6): 569 - 573.
[Abstract] [Full Text] [PDF]

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 Infect. Immun.Home page
H. Goldfine, S. J. Wadsworth, and N. C. Johnston
Activation of Host Phospholipases C and D in Macrophages after Infection with Listeria monocytogenes
Infect. Immun., October 1, 2000; 68(10): 5735 - 5741.
[Abstract] [Full Text] [PDF]

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 Plant CellHome page
J. M. Stone, J. E. Heard, T. Asai, and F. M. Ausubel
Simulation of Fungal-Mediated Cell Death by Fumonisin B1 and Selection of Fumonisin B1-Resistant (fbr) Arabidopsis Mutants
PLANT CELL, October 1, 2000; 12(10): 1811 - 1822.
[Abstract] [Full Text]

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 J. Lipid Res.Home page
C. P. Diggle, E. Pitt, P. Roberts, L. K. Trejdosiewicz, and J. Southgate
N-3 and n-6 polyunsaturated fatty acids induce cytostasis in human urothelial cells independent of p53 gene function
J. Lipid Res., September 1, 2000; 41(9): 1509 - 1515.
[Abstract] [Full Text]

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 J. Lipid Res.Home page
J. Bodennec, O. Koul, I. Aguado, G. Brichon, G. Zwingelstein, and J. Portoukalian
A procedure for fractionation of sphingolipid classes by solid-phase extraction on aminopropyl cartridges
J. Lipid Res., September 1, 2000; 41(9): 1524 - 1531.
[Abstract] [Full Text]

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 Cancer Res.Home page
V. E. Nava, O. Cuvillier, L. C. Edsall, K. Kimura, S. Milstien, E. P. Gelmann, and S. Spiegel
Sphingosine Enhances Apoptosis of Radiation-resistant Prostate Cancer Cells
Cancer Res., August 1, 2000; 60(16): 4468 - 4474.
[Abstract] [Full Text]

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 Toxicol SciHome page
L. D. Lehman-McKeeman and E. A. Gamsky
Choline Supplementation Inhibits Diethanolamine-Induced Morphological Transformation in Syrian Hamster Embryo Cells: Evidence for a Carcinogenic Mechanism
Toxicol. Sci., June 1, 2000; 55(2): 303 - 310.
[Abstract] [Full Text] [PDF]

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 JCBHome page
P. Tvrdik, R. Westerberg, S. Silve, A. Asadi, A. Jakobsson, B. Cannon, G. Loison, and A. Jacobsson
Role of a New Mammalian Gene Family in the Biosynthesis of Very Long Chain Fatty Acids and Sphingolipids
J. Cell Biol., May 1, 2000; 149(3): 707 - 718.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
R. A. ZAGER, K. M. BURKHART, and A. JOHNSON
Sphingomyelinase and Membrane Sphingomyelin Content: Determinants ofProximal Tubule Cell Susceptibility to Injury
J. Am. Soc. Nephrol., May 1, 2000; 11(5): 894 - 902.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
M. Tani, N. Okino, K. Mori, T. Tanigawa, H. Izu, and M. Ito
Molecular Cloning of the Full-length cDNA Encoding Mouse Neutral Ceramidase. A NOVEL BUT HIGHLY CONSERVED GENE FAMILY OF NEUTRAL/ALKALINE CERAMIDASES
J. Biol. Chem., April 6, 2000; 275(15): 11229 - 11234.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. Hanada, T. Hara, and M. Nishijima
Purification of the Serine Palmitoyltransferase Complex Responsible for Sphingoid Base Synthesis by Using Affinity Peptide Chromatography Techniques
J. Biol. Chem., March 17, 2000; 275(12): 8409 - 8415.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. Bernardo, O. Krut, K. Wiegmann, D. Kreder, M. Micheli, R. Schafer, A. Sickman, W. E. Schmidt, J. M. Schroder, H. E. Meyer, et al.
Purification and Characterization of a Magnesium-dependent Neutral Sphingomyelinase from Bovine Brain
J. Biol. Chem., March 10, 2000; 275(11): 7641 - 7647.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
E. M. Schmelz, M. C. Sullards, D. L. Dillehay, and A. H. Merrill Jr.
Colonic Cell Proliferation and Aberrant Crypt Foci Formation Are Inhibited by Dairy Glycosphingolipids in 1,2-Dimethylhydrazine-Treated CF1 Mice
J. Nutr., March 1, 2000; 130(3): 522 - 527.
[Abstract] [Full Text]

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 PhysiologyHome page
J. Pfeilschifter and A. Huwiler
Ceramides as Key Players in Cellular Stress Response
Physiology, February 1, 2000; 15(1): 11 - 15.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
E Genersch, K Hayess, Y Neuenfeld, and H Haller
Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways
J. Cell Sci., January 12, 2000; 113(23): 4319 - 4330.
[Abstract] [PDF]

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 J. Biol. Chem.Home page
S. An, Y. Zheng, and T. Bleu
Sphingosine 1-Phosphate-induced Cell Proliferation, Survival, and Related Signaling Events Mediated by G Protein-coupled Receptors Edg3 and Edg5
J. Biol. Chem., January 7, 2000; 275(1): 288 - 296.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
B. SÉGUI, C. BEZOMBES, E. URO-COSTE, J. A. MEDIN, N. ANDRIEU-ABADIE, N. AUGÉ, A. BROUCHET, G. LAURENT, R. SALVAYRE, J.-P. JAFFRÉZOU, et al.
Stress-induced apoptosis is not mediated by endolysosomal ceramide
FASEB J, January 1, 2000; 14(1): 36 - 47.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
B. Segui, N. Andrieu-Abadie, S. Adam-Klages, O. Meilhac, D. Kreder, V. Garcia, A. P. Bruno, J.-P. Jaffrezou, R. Salvayre, M. Kronke, et al.
CD40 Signals Apoptosis through FAN-regulated Activation of the Sphingomyelin-Ceramide Pathway
J. Biol. Chem., December 24, 1999; 274(52): 37251 - 37258.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
N. Okino, S. Ichinose, A. Omori, S. Imayama, T. Nakamura, and M. Ito
Molecular Cloning, Sequencing, and Expression of the Gene Encoding Alkaline Ceramidase from Pseudomonas aeruginosa. CLONING OF A CERAMIDASE HOMOLOGUE FROM MYCOBACTERIUM TUBERCULOSIS
J. Biol. Chem., December 17, 1999; 274(51): 36616 - 36622.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
P. Xia, M. A. Vadas, K.-A. Rye, P. J. Barter, and J. R. Gamble
High Density Lipoproteins (HDL) Interrupt the Sphingosine Kinase Signaling Pathway. A POSSIBLE MECHANISM FOR PROTECTION AGAINST ATHEROSCLEROSIS BY HDL
J. Biol. Chem., November 12, 1999; 274(46): 33143 - 33147.
[Abstract] [Full Text] [PDF]

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 JCBHome page
A. Olivera, T. Kohama, L. Edsall, V. Nava, O. Cuvillier, S. Poulton, and S. Spiegel
Sphingosine Kinase Expression Increases Intracellular Sphingosine-1-Phosphate and Promotes Cell Growth and Survival
J. Cell Biol., November 1, 1999; 147(3): 545 - 558.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
E. Kobrinsky, A. I. Spielman, S. Rosenzweig, and A. R. Marks
Ceramide triggers intracellular calcium release via the IP3 receptor in Xenopus laevis oocytes
Am J Physiol Cell Physiol, October 1, 1999; 277(4): C665 - C672.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
A. Sachinidis, R. Kettenhofen, S. Seewald, I. Gouni-Berthold, U. Schmitz, C. Seul, Y. Ko, and H. Vetter
Evidence That Lipoproteins Are Carriers of Bioactive Factors
Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2412 - 2421.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
M. BELLIO, A.-C. S. C. O LIVEIRA, C. S. MERMELSTEIN, M. A. M. CAPELLA, J. P. B. VIOLA, J.-P. LEVRAUD, G. A. DOSREIS, J. O. PREVIATO, and L. MENDONÇA-PREVIATO
Costimulatory action of glycoinositolphospholipids from Trypanosoma cruzi: increased interleukin 2 secretion and induction of nuclear translocation of the nuclear factor of activated T cells 1
FASEB J, September 1, 1999; 13(12): 1627 - 1636.
[Abstract] [Full Text]

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 J. Neurosci.Home page
H. Hida, S. Nagano, M. Takeda, and B. Soliven
Regulation of Mitogen-Activated Protein Kinases by Sphingolipid Products in Oligodendrocytes
J. Neurosci., September 1, 1999; 19(17): 7458 - 7467.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Kon, K. Sato, T. Watanabe, H. Tomura, A. Kuwabara, T. Kimura, K.-i. Tamama, T. Ishizuka, N. Murata, T. Kanda, et al.
Comparison of Intrinsic Activities of the Putative Sphingosine 1-Phosphate Receptor Subtypes to Regulate Several Signaling Pathways in Their cDNA-transfected Chinese Hamster Ovary Cells
J. Biol. Chem., August 20, 1999; 274(34): 23940 - 23947.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. Scorrano, V. Petronilli, F. Di Lisa, and P. Bernardi
Commitment to Apoptosis by GD3 Ganglioside Depends on Opening of the Mitochondrial Permeability Transition Pore
J. Biol. Chem., August 6, 1999; 274(32): 22581 - 22585.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
T. Yamashita, R. Wada, T. Sasaki, C. Deng, U. Bierfreund, K. Sandhoff, and R. L. Proia
A vital role for glycosphingolipid synthesis during development and differentiation
PNAS, August 3, 1999; 96(16): 9142 - 9147.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
A. FATATIS and R. J. MILLER
Cell cycle control of PDGF-induced Ca2+ signaling through modulation of sphingolipid metabolism
FASEB J, August 1, 1999; 13(11): 1291 - 1301.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
N. Auge, M. Nikolova-Karakashian, S. Carpentier, S. Parthasarathy, A. Negre-Salvayre, R. Salvayre, A. H. Merrill Jr., and T. Levade
Role of Sphingosine 1-Phosphate in the Mitogenesis Induced by Oxidized Low Density Lipoprotein in Smooth Muscle Cells via Activation of Sphingomyelinase, Ceramidase, and Sphingosine Kinase
J. Biol. Chem., July 30, 1999; 274(31): 21533 - 21538.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
N. Ancellin and T. Hla
Differential Pharmacological Properties and Signal Transduction of the Sphingosine 1-Phosphate Receptors EDG-1, EDG-3, and EDG-5
J. Biol. Chem., July 2, 1999; 274(27): 18997 - 19002.
[Abstract] [Full Text] [PDF]


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