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MBC in Press, published online ahead of print February 20, 2008
Mol. Biol. Cell 10.1091/mbc.E07-08-0811

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Submitted on August 21, 2007
Revised on January 28, 2008
Accepted on February 7, 2008

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 Signalling

David Dávila and Ignacio Torres-Aleman

Laboratory of Neuroendocrinology, Cajal Institute, CSIC; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Madrid, Spain

Monitoring Editor: Donald Newmeyer

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 µM hydrogen peroxide (H2O2) 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.

Address correspondence to: Ignacio Torres-Aleman (torres{at}cajal.csic.es)






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