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Mol Biol Cell. 2008 May;19(5):2014-25. doi: 10.1091/mbc.E07-08-0811. Epub 2008 Feb 20.

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.

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  • 1Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain.

Abstract

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.

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