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J. Biol. Chem., Vol. 276, Issue 11, 8297-8305, March 16, 2001
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From the The role of the second messenger ceramide
in Fas-mediated death requires clarification. To address this issue, we
generated hepatocytes from paired acid sphingomyelinase
(ASMase; asmase)+/+ and
asmase
Natural Ceramide Reverses Fas Resistance of Acid
Sphingomyelinase
/ Hepatocytes*
,,
,,**
Laboratory of Signal Transduction, the
Departments of Radiation Oncology and ¶ Surgery, Memorial
Sloan-Kettering Cancer Center, New York, New York 10021 and the
§ Department of Immunology, St. Jude Children's Research
Hospital, Memphis, Tennessee 38105
/ mice.
asmase/ hepatocytes, derived
from 8-week-old mice, manifested normal sphingomyelin content and
normal morphological, biochemical, and biologic features. Nonetheless,
ASMase-deficient hepatocytes did not display rapid ceramide elevation
or apoptosis in response to Jo2 anti-Fas antibody.
asmase/ hepatocytes were not
inherently resistant to apoptosis because staurosporine, which did not
induce early ceramide elevation, stimulated a normal apoptotic
response. The addition of low nanomolar quantities of natural
C16-ceramide, which by itself did not induce apoptosis,
completely restored the apoptotic response to anti-Fas in
asmase/ hepatocytes. Other
sphingolipids did not replace natural ceramide and restore Fas
sensitivity. Overcoming resistance to Fas in
asmase/ hepatocytes by natural
ceramide is evidence that it is the lack of ceramide and not ASMase
which determines the apoptotic phenotype. The ability of natural
ceramide to rescue the phenotype without reversing the genotype
provides evidence that ceramide is obligate for Fas induction of
apoptosis in hepatocytes.
*
This work was supported by National Institutes of Health
Grants CA42385 (to R. K.), CA52462 (to Z. F.), CA72632 (to Y. F.), and CA61524 (to Y. F.) and by Deutsche Forschungsgemeinschaft Grant Gu
335/2-3 (to E. G.).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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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