The role of sphingolipids in the process of apoptosis is centred on the sphingomyelin (SM) cycle (Figure 2). The inducers of the sphingomyelin cycle include many agents that induce apoptosis and/or growth arrest in cells, and examples are: cytokines such as TNF-a, interleukin-1, and -y-interferon; Fas ligand; 1,25-dihydroxyvitamin D3; and environmental stresses such as ultraviolet radiation, serum withdrawal, and chemotherapeutic agents (2).
The initial finding pointing to sphingolipids in apoptosis was the observation that ceramide was often cytotoxic to U937 cells, resulting in DNA fragmentation (3), while closely related compounds such as dihydroceramide and diacylglycerol did not induce DNA fragmentation. Furthermore, recent studies have shown that ceramide acts as a lipid mediator in cells and has, for targets, a ceramide-activated protein kinase and a ceramide-activated protein phosphatase. Downstream of these effects are the caspases, Raf-1 and the ERKs (2, 4) (Figure 2). The generation of ceramide is thought to be from the hydrolysis of SM by the neutral sphingomyelinase (n-SMase) (5) and/or acid
6: Sphingolipids as messengers of cell death Stress Signal
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