Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans |
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Authors: | Deng Xinzhu Yin Xianglei Allan Richard Lu Diane D Maurer Carine W Haimovitz-Friedman Adriana Fuks Zvi Shaham Shai Kolesnick Richard |
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Affiliation: | Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA. |
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Abstract: | 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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