REQUIREMENT FOR CERAMIDE-INITIATED SAPK JNK SIGNALING IN STRESS-INDUCED APOPTOSIS/

The induction of programmed cell death, or apoptosis, involves activat ion of a signalling system, many elements of which remain unknown(1). The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger c eramide(2,3), is thought to mediate apoptosis in response to tumour-ne crosis factor (TNF)-alpha(2,3), to Fas ligand(4) and to X-rays(5). It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also s timulate a stress-activated protein kinase (SAPR/JNK)(6-12), the sphin gomyelin and SAPK/ JNK signalling systems may be coordinated in induct ion of apoptosis. Here we report that ceramide initiates apoptosis thr ough the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.