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

Overview

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.

publication date

  • September 10, 1998

Research

keywords

  • Apoptosis
  • Caspases
  • Membrane Glycoproteins
  • Mitogen-Activated Protein Kinases
  • fas Receptor

Identity

Scopus Document Identifier

  • 0032505127

Digital Object Identifier (DOI)

  • 10.1016/s0960-9822(07)00420-4

PubMed ID

  • 9740801

Additional Document Info

volume

  • 8

issue

  • 18