Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.
Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.
Gulbins
E
E
Institute of Physiology, University of Tuebingen, Germany.
Brenner
B
B
Schlottmann
K
K
Welsch
J
J
Heinle
H
H
Koppenhoefer
U
U
Linderkamp
O
O
Coggeshall
K M
KM
Lang
F
F
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003497:Cyclic N-Oxides; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells / Q000502:physiology*; D009589:Nitrogen Oxides / Q000494:pharmacology; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection; D019014:fas Receptor / Q000494:pharmacology*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D019014:fas Receptor; C029217:phenyl-N-tert-butylnitrone; D015689:Oncogene Protein p21(ras); D000111:Acetylcysteine