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Vol. 19, Issue 5, 2014-2025, May 2008

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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

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

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

Abbreviations used: H₂O₂, hydrogen peroxide; IGF-I, insulin-like growth factor I; JNK2, Jun-kinase 2; LDH, lactate dehydrogenase; PI, propidium iodide; PI3K, phosphatidyl inositol 3 kinase; ROS, reactive oxygen species.