ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation

Exp Cell Res. 2003 Feb 15;283(2):156-66. doi: 10.1016/s0014-4827(02)00033-2.


Excess ER stress induces caspase-12 activation and/or cytochrome c release, causing caspase-9 activation. Little is known about their relationship during ER stress-mediated cell death. Upon ER stress, P19 embryonal carcinoma (EC) cells showed activation of various caspases, including caspase-3, caspase-8, caspase-9, and caspase-12, and extensive DNA fragmentation. We examined the relationship between ER stress-mediated cytochrome c/caspase-9 and caspase-12 activation by using caspase-9- and caspase-8-deficient mouse embryonic fibroblasts and a P19 EC cell clone [P19-36/12 (-) cells] lacking expression of caspase-12. Caspase-9 and caspase-8 deficiency inhibited and delayed the onset of DNA fragmentation but did not inhibit caspase-12 processing induced by ER stress. P19-36/12 (-) cells underwent apoptosis upon ER stress, with cytochrome c release and caspase-8 and caspase-9 activation. The dominant negative form of FADD and z-VAD-fmk inhibited caspase-8, caspase-9, Bid processing, cytochrome c release, and DNA fragmentation induced by ER stress, suggesting that caspase-8 and caspase-9 are the main caspases involved in ER stress-mediated apoptosis of P19-36/12 (-) cells. Caspase-8 deficiency also inhibited the cytochrome c release induced by ER stress. Thus, in parallel with the caspase-12 activation, ER stress triggers caspase-8 activation, resulting in cytochrome c/caspase-9 activation via Bid processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / metabolism
  • Caspase 12
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cytochrome c Group / metabolism*
  • DNA Fragmentation
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology*
  • Enzyme Activation / physiology
  • Immunologic Techniques
  • Mice
  • Protein Processing, Post-Translational / physiology
  • Signal Transduction
  • Tumor Cells, Cultured


  • BH3 Interacting Domain Death Agonist Protein
  • Bid protein, mouse
  • Carrier Proteins
  • Cytochrome c Group
  • Casp12 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 12
  • Caspase 8
  • Caspase 9
  • Caspases