CERAMIDE SIGNALING IN APOPTOSIS

The sphingomyelin pathway is a ubiquitous, evolutionarily conserved si gna ii ng system initiated by hydrolysis of the plasma membrane phosph olipid sphingomyelin to generate ceramide. Ceramide acts as a second m essenger in activating the apoptotic cascade. Diverse cytokine recepto rs and environmental stresses utilize ceramide to signal apoptosis. In several cell systems ceramide links to the stress-activated protein k inase (SAPK)/c-jun kinase (JNK) cascade to signal apoptosis. The engag ement of the sphingomyelin pathway in signaling apoptosis is tightly r egulated by anti-apoptotic central mechanisms, and the balance between pro- and anti-apoptotic systems determines the magnitude of the apopt otic response in vitro and in vivo. This review describes the known el ements and molecular ordering of ceramide-mediated apoptosis and the a nti-apoptotic mechanisms that regulate its expression. Understanding o f pro- and anti-apoptotic signaling involved in ceramide-mediated apop tosis and the modes of their co-ordinated Function may yield opportuni ties for pharmacological interventions with potential for clinical app lications.