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J Biol Chem, Vol. 275, Issue 12, 8650-8656, March 24, 2000

CD95(Fas/APO-1) Signals Ceramide Generation Independent of the Effector Stage of Apoptosis*

Carsten GrullichDagger , M. Cameron Sullards§, Zvi Fuks, Alfred H. Merrill Jr.§, and Richard KolesnickDagger ||

From the Dagger  Laboratory of Signal Transduction and  Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and the § Department of Biochemistry, Emory University, Atlanta, Georgia 30322

Although numerous studies document caspase-independent ceramide generation preceding apoptosis upon environmental stress, the molecular ordering of ceramide generation during cytokine-induced apoptosis remains uncertain. Here, we show that CD95-induced ceramide elevation occurs during the initiation phase of apoptosis. We titrated down the amount of FADD transfected into HeLa and 293T cells until it was insufficient for apoptosis, although cycloheximide (CHX) still triggered the effector phase. Even in the absence of CHX, ceramide levels increased rapidly, peaking at 2.7 ± 0.2-fold of control 8 h post-transfection. Dominant negative FADD failed to confer ceramide generation or CHX-mediated apoptosis. Ceramide generation induced by FADD was initiator caspase-dependent, being blocked by crmA. Limited pro-caspase 8 overexpression also increased ceramide levels 2.7 ± 0.2-fold, yet failed, without CHX, to initiate apoptosis. Expression of membrane-targeted oligomerized CD-8 caspase 8 induced apoptosis without CHX, yet elevated ceramide only to a level equivalent to limited pro-caspase 8 transfection. Ceramide elevations were detected concurrently by diacylglycerol kinase and electrospray tandem mass spectrometry. These investigations provide evidence that ceramide generation is initiator caspase-dependent and occurs prior to commitment to the effector phase of apoptosis, definitively ordering ceramide as proximal in CD95 signaling.

* This work was supported by Grants CA42385 and CA52462 (to R. K. and Z. F., respectively) from the National Institutes of Health, Grant GM46368 (to A. M.), and by a fellowship of Deutsche Krebshilfe (to C. 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.

|| 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 © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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