Evidence for a novel, caspase-8-independent, Fas death domain-mediated apoptotic pathway

Hanping Feng, Yi - Zeng, Michael W. Graner, Luke Whitesell, Emmanuel Katsanis

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Certain caspase-8 null cell lines demonstrate resistance to Fas-induced apoptosis, indicating that the Fas/FasL apoptotic pathway may be caspase-8-dependent. Some reports, however, have shown that Fas induces cell death independent of caspase-8. Here we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cells express procaspase-3, -8, and -9, which were activated upon the dimerization of Fas death domain. Bid was cleaved and mitochondrial transmembrane potential was disrupted in this apoptotic process. All apoptotic events were completely blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK, but not by other peptide caspase inhibitors. Cyclosporin A (CsA), which inhibits mitochondrial transition pore permeability, blocked neither pore permeability disruption nor caspase activation. However, CsA plus caspase-8 inhibitor blocked all apoptotic events of 12B1-D1 induced by Fas death domain dimerization. Our data therefore suggest that there is a novel, caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly.

Original languageEnglish (US)
Pages (from-to)41-51
Number of pages11
JournalJournal of Biomedicine and Biotechnology
Volume2004
Issue number1
DOIs
StatePublished - Apr 27 2004

Fingerprint

Caspase 8
Caspase Inhibitors
Dimerization
Cyclosporine
Mitochondria
Null Lymphocytes
Cell death
Caspases
Caspase 3
Death Domain
Membrane Potentials
Chemical activation
Cells
Permeability
Apoptosis
Cell Death
Peptides
Cell Line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Genetics
  • Applied Microbiology and Biotechnology

Cite this

Evidence for a novel, caspase-8-independent, Fas death domain-mediated apoptotic pathway. / Feng, Hanping; Zeng, Yi -; Graner, Michael W.; Whitesell, Luke; Katsanis, Emmanuel.

In: Journal of Biomedicine and Biotechnology, Vol. 2004, No. 1, 27.04.2004, p. 41-51.

Research output: Contribution to journalArticle

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AU - Katsanis, Emmanuel

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AB - Certain caspase-8 null cell lines demonstrate resistance to Fas-induced apoptosis, indicating that the Fas/FasL apoptotic pathway may be caspase-8-dependent. Some reports, however, have shown that Fas induces cell death independent of caspase-8. Here we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cells express procaspase-3, -8, and -9, which were activated upon the dimerization of Fas death domain. Bid was cleaved and mitochondrial transmembrane potential was disrupted in this apoptotic process. All apoptotic events were completely blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK, but not by other peptide caspase inhibitors. Cyclosporin A (CsA), which inhibits mitochondrial transition pore permeability, blocked neither pore permeability disruption nor caspase activation. However, CsA plus caspase-8 inhibitor blocked all apoptotic events of 12B1-D1 induced by Fas death domain dimerization. Our data therefore suggest that there is a novel, caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly.

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