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Curr Biol. 1998 Sep 10;8(18):1001-8.

Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade.

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1
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

BACKGROUND:

Fas (APO-1/CD95) is a member of the tumor necrosis factor receptor (TNF-R) family and induces apoptosis when crosslinked with either Fas ligand or agonistic antibody (Fas antibody). The Fas-Fas ligand system has an important role in the immune system where it is involved in the downregulation of immune responses and the deletion of peripheral autoreactive T lymphocytes. The intracellular domain of Fas interacts with several proteins including FADD (MORT-1), DAXX, RIP, FAF-1, FAP-1 and Sentrin. The adaptor protein FADD can, in turn, interact with the cysteine protease caspase-8 (FLICE/MACH/Mch5).

RESULTS:

In a genetic screen for essential components of the Fas-mediated apoptotic cascade, we isolated a Jurkat T lymphocyte cell line deficient in caspase-8 that was completely resistant to Fas-induced apoptosis. Complementation of this cell line with wild-type caspase-8 restored Fas-mediated apoptosis. Fas activation of multiple caspases and of the stress kinase p38 and c-Jun NH2-terminal kinase (JNK) was completely blocked in the caspase-8-deficient cell line. Furthermore, the cell line was severely deficient in cell death induced by TNF-alpha and was partially deficient in cell death induced by ultraviolet irradiation, adriamycin and etoposide.

CONCLUSIONS:

This study provides the first genetic evidence that caspase-8 occupies an essential and apical position in the Fas signaling pathway and suggests that caspase-8 may participate broadly in multiple apoptotic pathways.

PMID:
9740801
DOI:
10.1016/s0960-9822(07)00420-4
[Indexed for MEDLINE]
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