Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling

Mol Biol Cell. 2008 May;19(5):2014-25. doi: 10.1091/mbc.e07-08-0811. Epub 2008 Feb 20.


Oxidative stress kills neurons by stimulating FOXO3, a transcription factor whose activity is inhibited by insulin-like growth factor I (IGF-I), a wide-spectrum neurotrophic signal. Because recent evidence has shown that oxidative stress blocks neuroprotection by IGF-I, we examined whether attenuation of IGF-I signaling is linked to neuronal death by oxidative stress, as both events may contribute to neurodegeneration. We observed that in neurons, activation of FOXO3 by a burst of oxidative stress elicited by 50 muM hydrogen peroxide (H(2)O(2)) recruited a two-pronged pathway. A first, rapid arm attenuated AKT inhibition of FOXO3 through p38 MAPK-mediated blockade of IGF-I stimulation of AKT. A second delayed arm involved activation of FOXO3 by Jun-kinase 2 (JNK2). Notably, blockade of IGF-I signaling through p38 MAPK was necessary for JNK2 to activate FOXO3, unveiling a competitive regulatory interplay between the two arms onto FOXO3 activity. Therefore, an abrupt rise in oxidative stress activates p38 MAPK to tilt the balance in a competitive AKT/JNK2 regulation of FOXO3 toward its activation, eventually leading to neuronal death. In view of previous observations linking attenuation of IGF-I signaling to other causes of neuronal death, these findings suggest that blockade of trophic input is a common step in neuronal death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Enzyme Activation / drug effects
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology*
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / enzymology*
  • Oxidative Stress / drug effects*
  • Phosphoserine / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • FOXO3 protein, rat
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Phosphoserine
  • Insulin-Like Growth Factor I
  • Hydrogen Peroxide
  • Mitogen-Activated Protein Kinase 9
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases