Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis

doi:10.1084/jem.180.2.525

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Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis

A Haimovitz-Friedman, CC Kan, D Ehleiter, RS Persaud, M McLoughlin, Z Fuks and RN Kolesnick
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York 10021.

Recent investigations provided evidence that the sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor alpha (TNF-alpha) in several hematopoietic and nonhematopoietic cells. In this pathway, TNF-receptor interaction initiates sphingomyelin hydrolysis to ceramide by a sphingomyelinase. Ceramide acts as a second messenger stimulating a ceramide-activated serine/threonine protein kinase. The present studies show that ionizing radiation, like TNF, induces rapid sphingomyelin hydrolysis to ceramide and apoptosis in bovine aortic endothelial cells. Elevation of ceramide with exogenous ceramide analogues was sufficient for induction of apoptosis. Protein kinase C activation blocked both radiation-induced sphingomyelin hydrolysis and apoptosis, and apoptosis was restored by ceramide analogues added exogenously. Ionizing radiation acted directly on membrane preparations devoid of nuclei, stimulating sphingomyelin hydrolysis enzymatically through a neutral sphingomyelinase. These studies provide the first conclusive evidence that apoptotic signaling can be generated by interaction of ionizing radiation with cellular membranes and suggest an alternative to the hypothesis that direct DNA damage mediates radiation-induced cell kill.
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Faris, M., Latinis, K. M., Kempiak, S. J., Koretzky, G. A., Nel, A. (1998). Stress-Induced Fas Ligand Expression in T Cells Is Mediated through a MEK Kinase 1-Regulated Response Element in the Fas Ligand Promoter. Mol. Cell. Biol. 18: 5414-5424 [Abstract] [Full Text]
Hu, Z.-B., Minden, M.D., McCulloch, E.A. (1998). Phosphorylation of BCL-2 After Exposure of Human Leukemic Cells to Retinoic Acid. Blood 92: 1768-1775 [Abstract] [Full Text]
Kelly, M. L., Tang, Y., Rosensweig, N., Clejan, S., Beckman, B. S. (1998). Granulocyte-Macrophage Colony-Stimulating Factor Rescues TF-1 Leukemia Cells From Ionizing Radiation-Induced Apoptosis Through a Pathway Mediated by Protein Kinase Calpha. Blood 92: 416-424 [Abstract] [Full Text]
Gotoh, Y., Cooper, J. A. (1998). Reactive Oxygen Species- and Dimerization-induced Activation of Apoptosis Signal-regulating Kinase 1�in Tumor Necrosis Factor-alpha Signal Transduction. J. Biol. Chem. 273: 17477-17482 [Abstract] [Full Text]
Marekov, L. N., Steinert, P. M. (1998). Ceramides Are Bound to Structural Proteins of the Human Foreskin Epidermal Cornified Cell Envelope. J. Biol. Chem. 273: 17763-17770 [Abstract] [Full Text]
Suy, S., Mitchell, J. B., Ehleiter, D., Haimovitz-Friedman, A., Kasid, U. (1998). Nitroxides Tempol and Tempo Induce Divergent Signal Transduction Pathways in MDA-MB 231�Breast Cancer Cells. J. Biol. Chem. 273: 17871-17878 [Abstract] [Full Text]
Boland, M. P., O'Neill, L. A.�J. (1998). Ceramide Activates NFkappa B by Inducing the Processing of p105. J. Biol. Chem. 273: 15494-15500 [Abstract] [Full Text]
Liu, B., Andrieu-Abadie, N., Levade, T., Zhang, P., Obeid, L. M., Hannun, Y. A. (1998). Glutathione Regulation of Neutral Sphingomyelinase in Tumor Necrosis Factor-alpha -induced Cell Death. J. Biol. Chem. 273: 11313-11320 [Abstract] [Full Text]
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