Ceramide signaling in apoptosis

The sphingomyelin pathway is a ubiquitous, evolutionarily conserved signaling system initiated by hydrolysis of the plasma membrane phospholipid sphingomyelin to generate ceramide. Ceramide acts as a second messenger in activating the apoptotic cascade. Diverse Cytokine Receptors and environmental stresses utilize ceramide to signal Apoptosis. In several cell systems ceramide links to the stress-activated protein kinase (SAPK)/c-Jun kinase (JNK) cascade to signal Apoptosis. The engagement of the sphingomyelin pathway in signaling Apoptosis is tightly regulated by anti-apoptotic control mechanisms, and the balance between pro- and anti-apoptotic systems determines the magnitude of the apoptotic response in vitro and in vivo. This review describes the known elements and molecular ordering of ceramide-mediated Apoptosis and the anti-apoptotic mechanisms that regulate its expression. Understanding of pro- and anti-apoptotic signaling involved in ceramide-mediated Apoptosis and the modes of their co-ordinated function may yield opportunities for pharmacological interventions with potential for clinical applications.