Two CD95 (APO-1/Fas) signaling pathways

Carsten Scaffidi, Simone Fulda, Anu Srinivasan, Claudia Friesen, Feng Li, Kevin J. Tomaselli, Klaus Michael Debatin, Peter H. Krammer, Marcus E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2545 Scopus citations

Abstract

We have identified two cell types, each using almost exclusively one of two different CD95 (APO-1/Fas) signaling pathways, In type I cells, caspase-8 was activated within seconds and caspase-3 within 30 min of receptor engagement, whereas in type II cells cleavage of both caspases was delayed for ~ 60 min. However, both type I and type II cells showed similar kinetics of CD95-mediated apoptosis and loss of mitochondrial transmembrane potential (ΔΨ(m)). Upon CD95 triggering, all mitochondrial apoptogenic activities were blocked by Bcl-2 or Bcl-x(L) overexpression in both cell types. However, in type II but not type I cells, overexpression of Bcl-2 or Bcl-x(L) blocked caspase-8 and caspase-3 activation as well as apoptosis. In type I cells, induction of apoptosis was accompanied by activation of large amounts of caspase-8 by the death-inducing signaling complex (DISC), whereas in type II cells DISC formation was strongly reduced and activation of caspase-8 and caspase-3 occurred following the loss of ΔΨ(m). Overexpression of caspase-3 in the caspase-3-negative cell line MCF7-Fas, normally resistant to CD95-mediated apoptosis by overexpression of Bcl-x(L), converted these cells into true type I cells in which apoptosis was no longer inhibited by Bcl-x(L). In summary, in the presence of caspase-3 the amount of active caspase-8 generated at the DISC determines whether a mitochondria-independent apoptosis pathway is used (type I cells) or not (type II cells).

Original languageEnglish (US)
Pages (from-to)1675-1687
Number of pages13
JournalEMBO Journal
Volume17
Issue number6
DOIs
StatePublished - Mar 16 1998

Keywords

  • Apoptosis
  • Bcl-2
  • Caspases
  • Cytochrome c
  • Mitochondria

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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