ACID SPHINGOMYELINASE-DEFICIENT HUMAN LYMPHOBLASTS AND MICE ARE DEFECTIVE IN RADIATION-INDUCED APOPTOSIS

Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic respons e. Conclusive evidence for this paradigm, however, is lacking. In the present study, we used a genetic approach to address this issue direct ly. We show that lymphoblasts from Niemann-Pick patients, which have a n inherited deficiency of acid sphingomyelinase activity, fail to resp ond to ionizing radiation with ceramide generation and apoptosis. Thes e abnormalities are reversible upon restoration of acid sphingomyelina se activity by retroviral transfer of human acid sphingomyelinase cDNA . Acid sphingomyelinase knockout mice also expressed defects in radiat ion-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice revealed that acid sphingomyelinase-mediated apopto sis and p53-mediated apoptosis are likely distinct and independent. Th ese genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis.