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.
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.
Dávila
David
D
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain.
Torres-Aleman
Ignacio
I
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects*; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010768:Phosphoserine; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D048056:Mitogen-Activated Protein Kinase 9; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases