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Originally published In Press as doi:10.1074/jbc.M006353200 on October 12, 2000

J. Biol. Chem., Vol. 276, Issue 1, 442-448, January 5, 2001
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Cell Autonomous Apoptosis Defects in Acid Sphingomyelinase Knockout Fibroblasts*

José LozanoDagger , Silvia MenendezDagger , Albert MoralesDagger , Desiree Ehleiter§, Wen-Chieh Liao§, Rachel Wagman§, Adriana Haimovitz-Friedman§, Zvi Fuks§, and Richard Kolesnick*Dagger

From the Dagger  Laboratory of Signal Transduction and § Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 tumor necrosis factor alpha / actinomycin D 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, 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.

* This work was supported by National Institutes of Health Grants CA85714 (to R. K.) and CA52462 (to Z. F.), a Spanish Ministry of Education Fellowship (to J. L.), and a Spanish Ministry of Education-Fulbright Fellowship (to A. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel.: 212-639-7558; Fax: 212-639-2767.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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