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FADD Is Required for Multiple Signaling Events Downstream of the Receptor Fas¹

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 [P. J., M. S-A. W., C. J. K., J. B]; Dana Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts 02115 [C. J. K.]; Medical University of South Carolina, Charleston, South Carolina 29403 [P. S., Y. A. H.]; and Genzyme Corporation, Cambridge, Massachusetts 02139 [H. P. B]

To identify essential components of the Fas-induced apoptotic signaling pathway, Jurkat T lymphocytes were chemically mutagenized and selected for clones that were resistant to Fas-induced apoptosis. We obtained five cell lines that contain mutations in the adaptor FADD. All five cell lines did not express FADD by immunoblot analysis and were completely resistant to Fas-induced death. Complementation of the FADD mutant cell lines with wild-type FADD restored Fas-mediated apoptosis. Fas activation of caspase-2, caspase-3, caspase-7, and caspase-8 and the proteolytic cleavage of substrates such as BID, protein kinase C, and poly(ADP-ribose) polymerase were completely defective in the FADD mutant cell lines. In addition, Fas activation of the stress kinases p38 and c-Jun NH₂ kinase and the generation of ceramide in response to Fas ligation were blocked in the FADD mutant cell lines. These data indicate that FADD is essential for multiple signaling events downstream of Fas.

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