Role for ceramide as an endogenous mediator of Fasinduced cytotoxicity

Clifford G Tepper, Supriya Jayadev, Bin Liu, Alicja Bielawska, Robert Wolff, Shin Yonehara, Yusuf A. Hannun, Michael F Seldin

Research output: Contribution to journalArticle

321 Scopus citations

Abstract

Triggering of the Fas/APO-1 cell-surface receptor induces apoptosis through an uncharacterized chain of events. Exposure of Fas-sensitive cells to an agonist monoclonal antibody induced cell death and a 200-300% elevation in endogenous levels of the sphingolipid ceramide, a proposed intracellular mediator of apoptosis. In contrast, similar treatment of Fas-resistant cells caused insignificant changes in ceramide levels. Because resistant cell lines expressed the Fas antigen, these results indicate that these cells have a defect in the proximal signaling events leading to ceramide generation. Exposure of the resistant cell lines to a synthetic analog of ceramide induced apoptosis, thus bypassing Fas resistance and indicating that the signaling pathways downstream of ceramide were intact. Furthermore, activation of protein kinase C with the diacylglycerol analog phorbol 12-myristate 13-acetate significantly reduced Fas-induced cytotoxicity, suggesting opposing roles for ceramide and protein kinase C in regulation of apoptosis. These results provide evidence for ceramide as a necessary and sufficient lipid mediator of Fas-mediated apoptosis and suggest this process may be modulated via activation of additional signal-transduction pathways.

Original languageEnglish (US)
Pages (from-to)8443-8447
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number18
StatePublished - Aug 29 1995
Externally publishedYes

ASJC Scopus subject areas

  • General
  • Genetics

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    Tepper, C. G., Jayadev, S., Liu, B., Bielawska, A., Wolff, R., Yonehara, S., Hannun, Y. A., & Seldin, M. F. (1995). Role for ceramide as an endogenous mediator of Fasinduced cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 92(18), 8443-8447.