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Science 322 (5898): 110-115

Copyright © 2008 by the American Association for the Advancement of Science

Ceramide Biogenesis Is Required for Radiation-Induced Apoptosis in the Germ Line of C. elegans

Xinzhu Deng,1 Xianglei Yin,1 Richard Allan,1 Diane D. Lu,1 Carine W. Maurer,2 Adriana Haimovitz-Friedman,3 Zvi Fuks,3 Shai Shaham,2 Richard Kolesnick1*

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.

1 Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA.
2 Laboratory of Developmental Genetics, Rockefeller University, New York, NY, 10021, USA.
3 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

* To whom correspondence should be addressed. E-mail: r-kolesnick{at}ski.mskcc.org

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