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PMID: 8046331 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of experimental medicine ·Vol. 180 ·No. 2 ·1994-08-01 ·Pages 525-35

Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, Kolesnick RN

Abstract

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.

MeSH Terms
Animals Apoptosis/radiation effects Cattle Cell Membrane/metabolism,radiation effects Cells, Cultured Ceramides/biosynthesis DNA Damage Hematopoietic Stem Cells/cytology,metabolism,ultrastructure Humans Radiation, Ionizing Second Messenger Systems Signal Transduction Sphingomyelin Phosphodiesterase/metabolism Sphingomyelins/metabolism
Chemicals
Ceramides Sphingomyelins Sphingomyelin Phosphodiesterase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Haimovitz-Friedman A
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York 10021.
Kan C C
Ehleiter D
Persaud R S
McLoughlin M
Fuks Z
Kolesnick R N
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.180.2.525
Published
1994-08-01
Pages
525-35
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191598
Subset
IM
Grants
NCI NIH HHS · CA-42385 · United States
NCI NIH HHS · CA-52462 · United States
External Links
PubMed source DOI: 10.1084/jem.180.2.525 PMC Full Text View journal details
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