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J Biol Chem, Vol. 275, Issue 12, 9078-9084, March 24, 2000
From the The de novo pathway of sphingolipid
synthesis has been identified recently as a novel means of generating
ceramide during apoptosis. Furthermore, it has been suggested that the
activation of dihydroceramide synthase is responsible for increased
ceramide production through this pathway. In this study, accumulation
of ceramide mass in Molt-4 human leukemia cells by the chemotherapy agent etoposide was found to occur primarily due to activation of the
de novo pathway. However, when the cells were labeled with a substrate for dihydroceramide synthase in the presence of etoposide, there was no corresponding increase in labeled ceramide. Further investigation using a labeled substrate for serine
palmitoyltransferase, the rate-limiting enzyme in the pathway, resulted
in an accumulation of label in ceramide upon etoposide treatment. This
result suggests that the activation of serine palmitoyltransferase is
the event responsible for increased ceramide generation during de
novo synthesis initiated by etoposide. Importantly, the ceramide
generated from de novo synthesis appears to have a distinct
function from that induced by sphingomyelinase action in that it is not
involved in caspase-induced poly (ADP-ribose)polymerase proteolysis but does play a role in disrupting membrane integrity in this model system.
These results implicate serine palmitoyltransferase as the enzyme
controlling de novo ceramide synthesis during apoptosis and
begin to define a unique function of ceramide generated from this pathway.
Serine Palmitoyltransferase Regulates de Novo
Ceramide Generation during Etoposide-induced Apoptosis*
,,
Department of Biochemistry and Molecular
Biology, Medical University of South Carolina,
Charleston, South Carolina 29425, the § R. W. Johnson
Pharmaceutical Research Institute, Raritan, New Jersey 08869, and the ¶ Richard B. Russell Agricultural Research Station,
Athens, Georgia 30604
*
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: Dept. of
Biochemistry and Molecular and Biology, Medical University of South
Carolina, 173 Ashley Ave., Charleston, SC 29425. Fax:
843-953-0843.
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