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 response. Conclusive evidence for this paradigm, however, is lacking. In the present study, we used a genetic approach to address this issue directly. We show that lymphoblasts from Niemann-Pick patients, which have an inherited deficiency of acid sphingomyelinase activity, fail to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities are reversible up on restoration of acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Acid sphingomyelinase knockout mice also expressed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice revealed that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are likely distinct and independent. These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis.
Santana
P
P
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center New York, New York 10021, USA.
Peña
L A
LA
Haimovitz-Friedman
A
A
Martin
S
S
Green
D
D
McLoughlin
M
M
Cordon-Cardo
C
C
Schuchman
E H
EH
Fuks
Z
Z
Kolesnick
R
R
D000818:Animals; D017209:Apoptosis / Q000276:immunology* / Q000528:radiation effects; D002472:Cell Transformation, Viral; D002518:Ceramides / Q000096:biosynthesis / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology; D009542:Niemann-Pick Diseases / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000528:radiation effects; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D002518:Ceramides; D018076:DNA, Complementary; D016159:Tumor Suppressor Protein p53; D013108:Sphingomyelin Phosphodiesterase