Necrotic cell death in response to oxidant stress involves the activation of the apoptogenic caspase-8/bid pathway. Academic Article uri icon

Overview

MeSH

  • Adenocarcinoma
  • Animals
  • Antigens, CD95
  • BH3 Interacting Domain Death Agonist Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Cells, Cultured
  • Enzyme Inhibitors
  • Fas Ligand Protein
  • Fibroblasts
  • Gene Deletion
  • Humans
  • Lung
  • Lung Neoplasms
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxygen
  • Tumor Cells, Cultured

MeSH Major

  • Apoptosis
  • Carrier Proteins
  • Caspases
  • Intracellular Signaling Peptides and Proteins
  • Oxidative Stress

abstract

  • Human epithelial (A549) cells exposed to hyperoxia die by cellular necrosis. In the current study, we demonstrated the involvement of apoptogenic factors in epithelial cell necrosis in response to hyperoxia, including the formation of the Fas-related death-inducing signaling complex and initiation of mitochondria-dependent apoptotic pathways. We showed increased activation of both Bid and Bax in A549 cells subjected to hyperoxia. Bax activation involved a Bid-assisted conformational change. We discovered that the response to hyperoxia in vivo predominantly involved the activation of the Bid/caspase-8 pathway without apparent increases in Bax expression. Disruption of the Bid pathway by gene deletion protected against cell death in vivo and in vitro. Likewise, inhibition of caspase-8 by Flip also protected against cell death. Taken together, we have demonstrated the involvement of apoptogenic factors in epithelial cell responses to hyperoxia, despite a final outcome of cellular necrosis. We have, for the first time, identified a predominant role for the caspase-8/Bid pathway in signaling associated with hyperoxic lung injury and cell death in vivo and in vitro.

publication date

  • August 1, 2003

has subject area

  • Adenocarcinoma
  • Animals
  • Antigens, CD95
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases
  • Cells, Cultured
  • Enzyme Inhibitors
  • Fas Ligand Protein
  • Fibroblasts
  • Gene Deletion
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lung
  • Lung Neoplasms
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress
  • Oxygen
  • Tumor Cells, Cultured

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1074/jbc.M301624200

PubMed ID

  • 12754217

Additional Document Info

start page

  • 29184

end page

  • 29191

volume

  • 278

number

  • 31