Publication Date:
2008-10-04
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585063/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585063/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Xinzhu -- Yin, Xianglei -- Allan, Richard -- Lu, Diane D -- Maurer, Carine W -- Haimovitz-Friedman, Adriana -- Fuks, Zvi -- Shaham, Shai -- Kolesnick, Richard -- 2R01HD42680-06/HD/NICHD NIH HHS/ -- CA105125-03/CA/NCI NIH HHS/ -- CA85704/CA/NCI NIH HHS/ -- R01 CA085704/CA/NCI NIH HHS/ -- R01 CA085704-09/CA/NCI NIH HHS/ -- R01 HD042680/HD/NICHD NIH HHS/ -- R01 HD042680-07/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2008 Oct 3;322(5898):110-5. doi: 10.1126/science.1158111.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18832646" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
Caenorhabditis elegans/*cytology/genetics/*metabolism/physiology
;
Caenorhabditis elegans Proteins/genetics/*metabolism
;
Calcium-Binding Proteins/genetics/metabolism
;
Ceramides/biosynthesis/*metabolism/pharmacology
;
Genes, Helminth
;
Germ Cells/*cytology/metabolism/radiation effects
;
Mitochondria/metabolism
;
Mitochondrial Membranes/metabolism
;
Mutation
;
Nuclear Envelope/metabolism
;
Oxidoreductases/genetics/metabolism
;
Proto-Oncogene Proteins c-abl/genetics/metabolism
;
Proto-Oncogene Proteins c-bcl-2/metabolism
;
*Radiation, Ionizing
;
Repressor Proteins/metabolism
;
Tumor Suppressor Protein p53/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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