INHIBITION OF THE ANTI-APOPTOTIC PI(3)K AKT/BAD PATHWAY BY STRESS/

The initiation of apoptosis often transpires in the presence of agents that regulate cell survival. This study evaluated the effects of stre ss-induced ceramide on the anti-apoptotic activity of the phosphoinosi tide-3 kinase [PI(3)K] pathway. PI(3)K activity is directly down-regul ated by stress-induced ceramide in a dose-dependent manner with rapid kinetics and high specificity. Ceramide inhibition of PI(3)K is depend ent on acid-sphingomyelinase. Down-regulation of PI(3)K by ceramide re sults in inhibition of the kinase Akt and decreased phosphorylation of the death effector Bad. Thus, ceramide levels could act as a general apoptotic rheostat controlling cell survival by regulating PI(3)K anti -apoptotic effector mechanisms.