Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.

THE induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown1. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide2,3, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-α2,3, to Fas ligand4 and to X-rays5. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK) 6–12, the sphingomyelin and SAPK/ JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.