Journal
SCIENCE
Volume 322, Issue 5898, Pages 110-115Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1158111
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Funding
- [CA85704]
- [CA105125-03]
- [2R01HD42680-06]
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Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss- of- function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic ( developmental) apoptosis was unaffected, ionizing radiation- induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long- chain natural ceramide. Radiation- induced increase in the concentration of ceramide localized to mitochondria and was required for BH3- domain protein EGL-1-mediated displacement of CED-4 ( an APAF-1-like protein) from the CED-9 ( a Bcl-2 family member)/CED- 4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 ( the worm homolog of the tumor suppressor p53)-mediated accumulation of EGL- 1 and ceramide synthase-mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.
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