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Papers In Press, published online ahead of print October 12, 2000
Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Corresponding Author: r-kolesnick{at}ski.mskcc.org
A body of evidence suggests that stress-induced sphingomyelin hydrolysis to the second messenger ceramide initiates apoptosis in some cells. Although studies using lymphoblasts from Niemann-Pick disease patients or acid sphingomyelinase (ASMase)-deficient mice have provided genetic support for this hypothesis, these models have not been universally accepted as definitive. Here, we show that mouse embryonic fibroblasts (MEFs) prepared from asmase-/- mice manifest cell autonomous defects in apoptosis in response to several stresses. In particular, asmase-/- MEFs failed to generate ceramide and were totally resistant to radiation-induced apoptosis, but remained sensitive to staurosporine which did not induce ceramide. asmase-/- MEFs were also partially resistant to TNF
J. Biol. Chem, 10.1074/jbc.M006353200
Submitted on July 18, 2000
Revised on September 12, 2000
Accepted on October 12, 2000
Cell Autonomous Apoptosis Defects in Acid Sphingomyelinase Knockout Fibroblasts
/ActD and serum withdrawal. Thus, resistance to apoptosis in asmase-/- MEFs was not global but rather stress-type specific. Most importantly, the sensitivity to stress could be restored in the asmase-/- MEFs by administration of natural ceramide. Overcoming apoptosis resistance by natural ceramide is evidence that it is the lack of ceramide, and not ASMase, that determines apoptosis sensitivity. The ability to rescue the apoptotic phenotype without reversing the genotype by the product of the enzymatic deficiency provides proof that ceramide is obligate for apoptosis induction in response to some stresses.
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