C- and C-ceramides (N-acetylsphingosine and N-hexanoylsphingosine, respectively) abolished the stimulation of DNA synthesis by sphingosine 1-phosphate in rat fibroblasts. This inhibition by ceramide was partially prevented by insulin. C-ceramide did not alter the stimulation of DNA synthesis by insulin and decreased the sphingosine-induced stimulation by only 16%. The ceramides did not significantly modify the actions of sphingosine or sphingosine 1-phosphate in decreasing cAMP concentrations. C- and C-ceramides blocked the activation of phospholipase D by sphingosine 1-phosphate, and this inhibition was not affected by insulin. Okadaic acid decreased the activation of phospholipase D by sphingosine 1-phosphate and did not reverse the inhibitory effect of C-ceramide on this activation. Therefore, this effect of C-ceramide is unlikely to involve the stimulation of phosphoprotein phosphatase activity. Sphingosine did not activate phospholipase D activity significantly after 10 min. C-ceramide stimulated the conversion of exogenous [H]sphingosine 1-phosphate to sphingosine and ceramide in fibroblasts. Ceramides can inhibit some effects of sphingosine 1-phosphate by stimulating its degradation via a phosphohydrolase that also hydrolyzes phosphatidate. Furthermore, C- and C-ceramides stimulated ceramide production from endogenous lipids, and this could propagate the intracellular signal. This work demonstrates that controlling the production of ceramide versus sphingosine and sphingosine 1-phosphate after sphingomyelinase activation could have profound effects on signal transduction.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				V. Hinkovska-Galcheva, A. Clark, S. VanWay, J.-B. Huang, M. Hiraoka, A. Abe, M. Borofsky, R. G. Kunkel, T. Shanley, J. A. Shayman, et al. Ceramide kinase promotes Ca2+ signaling near IgG-opsonized targets and enhances phagolysosomal fusion in COS-1 cells J. Lipid Res., March 1, 2008; 49(3): 531 - 542. [Abstract] [Full Text] [PDF]

				L. Brizuela, M. Rabano, P. Gangoiti, N. Narbona, J. M. Macarulla, M. Trueba, and A. Gomez-Munoz Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K/PKB and MEK/ERK 1/2 pathways J. Lipid Res., October 1, 2007; 48(10): 2264 - 2274. [Abstract] [Full Text] [PDF]

				L. Brizuela, M. Rabano, A. Pena, P. Gangoiti, J. M. Macarulla, M. Trueba, and A. Gomez-Munoz Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion J. Lipid Res., June 1, 2006; 47(6): 1238 - 1249. [Abstract] [Full Text] [PDF]

				D. S. Wijesinghe, A. Massiello, P. Subramanian, Z. Szulc, A. Bielawska, and C. E. Chalfant Substrate specificity of human ceramide kinase J. Lipid Res., December 1, 2005; 46(12): 2706 - 2716. [Abstract] [Full Text] [PDF]

				A. Gomez-Munoz, J. Y. Kong, B. Salh, and U. P. Steinbrecher Ceramide-1-phosphate blocks apoptosis through inhibition of acid sphingomyelinase in macrophages J. Lipid Res., January 1, 2004; 45(1): 99 - 105. [Abstract] [Full Text] [PDF]

				D.-S. Kim, E.-S. Hwang, J.-E. Lee, S.-Y. Kim, S.-B. Kwon, and K.-C. Park Sphingosine-1-phosphate decreases melanin synthesis via sustained ERK activation and subsequent MITF degradation J. Cell Sci., May 1, 2003; 116(9): 1699 - 1706. [Abstract] [Full Text] [PDF]

				B. Salh, K. Assi, S. Huang, L. O'Brien, U. Steinbrecher, and A. Gomez-Munoz Dissociated ROS production and ceramide generation in sulfasalazine-induced cell death in Raw 264.7 cells J. Leukoc. Biol., October 1, 2002; 72(4): 790 - 799. [Abstract] [Full Text] [PDF]

				R. J. Cummings, N. L. Parinandi, A. Zaiman, L. Wang, P. V. Usatyuk, J. G. N. Garcia, and V. Natarajan Phospholipase D Activation by Sphingosine 1-Phosphate Regulates Interleukin-8 Secretion in Human Bronchial Epithelial Cells J. Biol. Chem., August 9, 2002; 277(33): 30227 - 30235. [Abstract] [Full Text] [PDF]

				E. Perez-Andres, M. Fernandez-Rodriguez, M. Gonzalez, A. Zubiaga, A. Vallejo, I. Garcia, C. Matute, S. Pochet, J. P. Dehaye, M. Trueba, et al. Activation of phospholipase D-2 by P2X7 agonists in rat submandibular gland acini J. Lipid Res., August 1, 2002; 43(8): 1244 - 1255. [Abstract] [Full Text] [PDF]

				S. Kim, H. Fyrst, and J. Saba Accumulation of Phosphorylated Sphingoid Long Chain Bases Results in Cell Growth Inhibition in Saccharomyces cerevisiae Genetics, December 1, 2000; 156(4): 1519 - 1529. [Abstract] [Full Text]

				A. Gomez-Munoz, J. S. Martens, and U. P. Steinbrecher Stimulation of Phospholipase D Activity by Oxidized LDL in Mouse Peritoneal Macrophages Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 135 - 143. [Abstract] [Full Text] [PDF]

				F. Wang, J. R. Van Brocklyn, J. P. Hobson, S. Movafagh, Z. Zukowska-Grojec, S. Milstien, and S. Spiegel Sphingosine 1-Phosphate Stimulates Cell Migration through a Gi-coupled Cell Surface Receptor. POTENTIAL INVOLVEMENT IN ANGIOGENESIS J. Biol. Chem., December 10, 1999; 274(50): 35343 - 35350. [Abstract] [Full Text] [PDF]

				R. T. Windh, M.-J. Lee, T. Hla, S. An, A. J. Barr, and D. R. Manning Differential Coupling of the Sphingosine 1-Phosphate Receptors Edg-1, Edg-3, and H218/Edg-5 to the Gi, Gq, and G12 Families of Heterotrimeric G Proteins J. Biol. Chem., September 24, 1999; 274(39): 27351 - 27358. [Abstract] [Full Text] [PDF]

				Y. Banno, H. Fujita, Y. Ono, S. Nakashima, Y. Ito, N. Kuzumaki, and Y. Nozawa Differential Phospholipase D Activation by Bradykinin and Sphingosine 1-Phosphate in NIH 3T3 Fibroblasts Overexpressing Gelsolin J. Biol. Chem., September 24, 1999; 274(39): 27385 - 27391. [Abstract] [Full Text] [PDF]

				A. Gómez-Muñoz, L. O'Brien, R. Hundal, and U. P. Steinbrecher Lysophosphatidylcholine stimulates phospholipase D activity in mouse peritoneal macrophages J. Lipid Res., June 1, 1999; 40(6): 988 - 993. [Abstract] [Full Text]

				G. Liu, L. Kleine, R. Nasrallah, and R. L. Hebert Bradykinin inhibits ceramide production and activates phospholipase D in rabbit cortical collecting duct cells Am J Physiol Renal Physiol, April 1, 1999; 276(4): F589 - F598. [Abstract] [Full Text] [PDF]

				Y.-L. Guo, B. Kang, L.-J. Yang, and J. R. Williamson Tumor necrosis factor-alpha and ceramide induce cell death through different mechanisms in rat mesangial cells Am J Physiol Renal Physiol, March 1, 1999; 276(3): F390 - F397. [Abstract] [Full Text] [PDF]

				J. R. Van Brocklyn, Z. Tu, L. C. Edsall, R. R. Schmidt, and S. Spiegel Sphingosine 1-Phosphate-induced Cell Rounding and Neurite Retraction Are Mediated by the G Protein-coupled Receptor H218 J. Biol. Chem., February 19, 1999; 274(8): 4626 - 4632. [Abstract] [Full Text] [PDF]

				E. J. Goetzl, Y. Kong, and B. Mei Lysophosphatidic Acid and Sphingosine 1-Phosphate Protection of T Cells from Apoptosis in Association with Suppression of Bax J. Immunol., February 15, 1999; 162(4): 2049 - 2056. [Abstract] [Full Text] [PDF]

				V. Tz. Hinkovska-Galcheva, L. A. Boxer, P. J. Mansfield, D. Harsh, A. Blackwood, and J. A. Shayman The Formation of Ceramide-1-phosphate during Neutrophil Phagocytosis and Its Role in Liposome Fusion J. Biol. Chem., December 11, 1998; 273(50): 33203 - 33209. [Abstract] [Full Text] [PDF]

				R. Roberts, V. A. Sciorra, and A. J. Morris Human Type 2 Phosphatidic Acid Phosphohydrolases. SUBSTRATE SPECIFICITY OF THE TYPE 2a, 2b, AND 2c ENZYMES AND CELL SURFACE ACTIVITY OF THE 2a ISOFORM J. Biol. Chem., August 21, 1998; 273(34): 22059 - 22067. [Abstract] [Full Text] [PDF]

				J. R. Van Brocklyn, M.-J. Lee, R. Menzeleev, A. Olivera, L. Edsall, O. Cuvillier, D. M. Thomas, P. J.P. Coopman, S. Thangada, C. H. Liu, et al. Dual Actions of Sphingosine-1-Phosphate: Extracellular through the Gi-coupled Receptor Edg-1 and Intracellular to Regulate Proliferation and Survival J. Cell Biol., July 13, 1998; 142(1): 229 - 240. [Abstract] [Full Text] [PDF]

				Y. Ruan, H. Kan, J.-H. Parmentier, S. Fatima, L. F. Allen, and K. U. Malik Alpha-1A Adrenergic Receptor Stimulation with Phenylephrine Promotes Arachidonic Acid Release by Activation of Phospholipase D in Rat-1 Fibroblasts: Inhibition by Protein Kinase A J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 576 - 585. [Abstract] [Full Text]

				L. Frago, Y Leon, E. de la Rosa, A Gomez-Munoz, and I Varela-Nieto Nerve growth factor and ceramides modulate cell death in the early developing inner ear J. Cell Sci., January 3, 1998; 111(5): 549 - 556. [Abstract] [PDF]

				T. Ariga, W. D. Jarvis, and R. K. Yu Role of sphingolipid-mediated cell death in neurodegenerative diseases J. Lipid Res., January 1, 1998; 39(1): 1 - 16. [Abstract] [Full Text]

				M. Kai, I. Wada, S.-i. Imai, F. Sakane, and H. Kanoh Cloning and Characterization of Two Human Isozymes of Mg2+-independent Phosphatidic Acid Phosphatase J. Biol. Chem., September 26, 1997; 272(39): 24572 - 24578. [Abstract] [Full Text] [PDF]

				J. Ginsberg, S. Gupta, W. C. Matowe, L. Kline, and D. N. Brindley Activation of Phospholipase D in FRTL-5 Thyroid Cells by Forskolin and Dibutyryl-Cyclic Adenosine Monophosphate Endocrinology, September 1, 1997; 138(9): 3645 - 3651. [Abstract] [Full Text] [PDF]

				Y. Ruan, H. Kan, and K. U. Malik J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1038 - 1046. [Abstract] [Full Text]

				D. A. Dillon, X. Chen, G. M. Zeimetz, W.-I. Wu, D. W. Waggoner, J. Dewald, D. N. Brindley, and G. M. Carman Mammalian Mg2+-independent Phosphatidate Phosphatase (PAP2) Displays Diacylglycerol Pyrophosphate Phosphatase Activity J. Biol. Chem., April 18, 1997; 272(16): 10361 - 10366. [Abstract] [Full Text] [PDF]

				E. I.P. de Chaves, M. Bussiere, D. E. Vance, R. B. Campenot, and J. E. Vance Elevation of Ceramide within Distal Neurites Inhibits Neurite Growth in Cultured Rat Sympathetic Neurons J. Biol. Chem., January 31, 1997; 272(5): 3028 - 3035. [Abstract] [Full Text] [PDF]

				A. Abousalham, C. Liossis, L. O'Brien, and D. N. Brindley Cell-permeable Ceramides Prevent the Activation of Phospholipase D by ADP-ribosylation Factor and RhoA J. Biol. Chem., January 10, 1997; 272(2): 1069 - 1075. [Abstract] [Full Text] [PDF]

				Y. A. Hannun Functions of Ceramide in Coordinating Cellular Responses to Stress Science, December 13, 1996; 274(5294): 1855 - 1859. [Abstract] [Full Text]

				H. M. Wright and K. U. Malik Prostacyclin Formation Elicited by Endothelin-1 in Rat Aorta Is Mediated via Phospholipase D Activation and Not Phospholipase C or A2 Circ. Res., August 1, 1996; 79(2): 271 - 276. [Abstract] [Full Text]

				D. W. Waggoner, A. Gomez-Munoz, J. Dewald, and D. N. Brindley Phosphatidate Phosphohydrolase Catalyzes the Hydrolysis of Ceramide 1-Phosphate, Lysophosphatidate, and Sphingosine 1-Phosphate J. Biol. Chem., July 12, 1996; 271(28): 16506 - 16509. [Abstract] [Full Text] [PDF]