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Letters to Nature
Nature 380, 75 - 79 (07 March 1996); doi:10.1038/380075a0

Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis

Marcel Verheij*, Ron Bose, Xin Hua Lin, Bei Yao, W. David Jarvis§, Steven Grant§, Michael J. Birrer, Eva Szabo, Leonard I. Zon, John M. Kyriakis£, Adriana Haimovitz-Friedman*, Zvi Fuks* & Richard N. Kolesnickstar

* Department of Radiation Oncology and Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
§ Department of Medicine, Division of Hematology–Oncology, Medical College of Virginia, 1101 East Marshall Street, Richmond, Virginia 23298, USA
Biomarkers and Prevention Research Branch, Division of Cancer Prevention and Control, National Cancer Institute, 9610 Medical Center Drive, Rockville, Maryland 20850, USA
Division of Hematology–Oncology, Children's Hospital and Dana-Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Howard Hughes Medical Institute, Children's Hospital, 300 Longwood Avenue, Enders 780, Boston, Massachusetts 02115, USA
£ Diabetes Research Laboratory, Medical Services, Massachusetts General Hospital East, 149 13th Street, Charlestown, Massachusetts 02129, USA
Present address: Department of Radiation Therapy, Antoni v. Leeuwenhoekhuis/The Netherlands Cancer Institute, Amsterdam, The Netherlands.
star To whom correspondence should be addressed.

THE induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown1. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide2,3, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-α2,3, to Fas ligand4 and to X-rays5. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK) 6–12, the sphingomyelin and SAPK/ JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.

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