ArticleMolecular biology of the cell2008
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.
Article in Molecular biology of the cell, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 94 citations in OpenAlex.
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- CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats.The Korean journal of internal medicine · 2023Article
- The Expression of FOXO3a as a Forensic Diagnostic Tool in Cases of Traumatic Brain Injury: An Immunohistochemical Study.International journal of molecular sciences · 2023Article
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- Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Article
- MicroRNA-137-3p Protects PC12 Cells Against Oxidative Stress by Downregulation of Calpain-2 and nNOS.Cellular and molecular neurobiology · 2021Article
- Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2021Review
- Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations.EMBO molecular medicine · 2020Article
- Oxidative Stress in Autism Spectrum Disorder.Molecular neurobiology · 2020Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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