Trends in Biochemical Sciences
Ceramide in apoptosis—does it really matter?
Section snippets
Signaling to sphingomyelinases
A number of stimuli have been reported to increase cellular ceramide levels (Fig. 2). Among the more prominent inducers are tumor necrosis factor (TNF), Fas-ligand (FasL), 1,25-dihydroxyvitamin D, ionizing radiation and various chemotherapeutic agents1, 2, 3. In some cases, the increase in ceramide levels is due to enhanced de novo synthesis[14]; in the majority, however, one or more of the cellular SMases are activated. The most extensively studied system is the activation of aSMase and nSMase
Ceramide effectors...
The products of the sphingomyelinase reaction, irrespective of the SMase isoform involved, are phosphorylcholine and ceramide (Fig. 1). Whereas the soluble phosphorylcholine rapidly diffuses away from the reaction site and is hydrolyzed to yield choline, ceramide is very hydrophobic and remains attached to the membrane. Ceramide is the sphingolipid analog of diacylglycerol (DAG), a second messenger derived from phosphatidylinositol 4,5-bisphosphate. DAG usually exerts its effect by binding to
and ceramide effects
The effects of exposure to ceramide or ectopic activation of sphingomyelinases are as diverse as the immediate downstream effectors of ceramide. Depending on the cell line used and the experimental setup, the effects range from induction of apoptosis, cell-cycle arrest and selective induction of the JNK pathway to increased cell survival, cell proliferation and selective induction of the ERK pathway2, 3, 33. Whether or not ceramide activates the proinflammatory transcription factor NF-κB is
DAG-kinase—a deceptive enzyme?
Proponents of a role for ceramide in apoptotic signaling rely on a chain of arguments that (when simplified) can be described as follows. Various apoptotic stimuli lead to activation of sphingomyelinase; sphingomyelinase generates ceramide; ceramide can induce apoptosis: ergo, ceramide is a second messenger in cell-death signaling. However, several recent findings challenge this point of view. A severe blow was dealt by the demonstration that the assay generally used for measuring cellular
Perspectives
As the signaling mechanisms that lead from (death-)receptor activation to apoptotis become better understood, it appears that ceramide does not really fit anywhere on the map. The receptor-proximal chain of events[16], at least, is known in sufficient detail for us to appreciate that TNF- or FasL-induced activation of the early caspases requires neither sphingomyelinases nor ceramide. The possibility that ceramide is generated early in the response to TNF or FasL cannot be excluded, although
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