Ceramide and cellular stress–induced apoptosis.

Ceramide is involved in cellular stress responses implicated in apoptosis, growth inhibition, and differentiation. The major source of ceramide is hydrolysis of sphingomyelin by SMases. De novo synthesis via ceramide synthase may also lead to the generation of ceramide. Ceramide acts as a catalyst for apoptosis through the consecutive activation of MEKK1, SEK1, JNK, c-Jun, and death-inducing ligands such as CD95-L. BAD, a proapoptotic Bcl-2 family member, is induced by a ceramide-mediated pathway involving CAPK, Ras, c-Raf-1, and MEK1. Other mediators of ceramide-induced apoptosis are ROS and the ganglioside GD3, which both affect mitochondria. Ceramide acts also upstream of the antiapoptotic kinase Akt, leading to a decrease in its activity. Activation of the stress response by ceramide leads to either survival or apoptosis. Members of this signaling cascade are CAPK, Ras, c-Raf-1, MEK1, PKC-ζ, JNK, and NF-κB. SPP results from the catabolic pathway for ceramide and acts as a second messenger in cellular proliferation and survival.