Short-chain ceramide-1-phosphates are novel stimulators of DNA synthesis and cell division: antagonism by cell-permeable ceramides.
Ceramide and ceramide-1-phosphate are sphingolipid analogues of diacylglycerol and phosphatidate, respectively, and they are putative second messengers of agonist-stimulated sphingomyelin metabolism. The interactions of exogenous cell-permeable ceramides and ceramide-1-phosphates in modifying DNA synthesis and signal transduction were investigated in Rat-1 fibroblasts. C2- and C8-Ceramide-1-phosphates (N-acetylsphingosine-1-phosphate and N-octanoylsphingosine-1-phosphate, respectively) at 1-10 microM stimulated DNA synthesis and cell division. This effect was blocked by cell-permeable ceramides. C2-Ceramide stimulated the conversion of exogenous C8-ceramide-1-phosphate to C8-ceramide, with very little production of sphingosine or sphingosine-1-phosphate. This mechanism may be partly responsible for preventing the stimulation of DNA synthesis. Unlike phosphatidate or lyso-phosphatidate, concentrations of C8-ceramide-1-phosphate that stimulated DNA synthesis did not inhibit adenylate cyclase activity, nor did they increase the activities of phospholipase D or mitogen-activated protein kinases (42- and 44 kDa isoforms). Although ceramide-1-phosphate can be considered as an analogue of phosphatidate, the effects of this compound on signal transduction differ considerably from those of phosphatidate. This work demonstrates that short-chain ceramide-1-phosphates can be used as novel external agonists that can stimulate DNA synthesis. This effect can be counteracted by short-chain ceramides.
Gomez-Muñoz
A
A
Department of Biochemistry (Signal Transduction Laboratories), University of Alberta, Edmonton, Canada.
Duffy
P A
PA
Martin
A
A
O'Brien
L
L
Byun
H S
HS
Bittman
R
R
Brindley
D N
DN
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002463:Cell Membrane Permeability; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D051381:Rats; D015290:Second Messenger Systems; D013109:Sphingomyelins / Q000378:metabolism
D002518:Ceramides; D010712:Phosphatidic Acids; D013109:Sphingomyelins; C065576:ceramide 1-phosphate; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010739:Phospholipase D