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Science Forum Index » Life Extension Forum » Neuronal Death by Oxidative Stress Involves Activation...
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 Posted: Wed May 14, 2008 11:47 am |
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I should add that p38MAPK activation is involved in cell death. The
study I cited involves a survival pathway via beta-catenin.
Mol Biol Cell. 2008 May;19(5):2014-25. Epub 2008 Feb 20. Links
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.Dávila D, Torres-Aleman I.
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de
Investigaciones Cientificas (CSIC); Centro de Investigación Biomédica
en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid,
Spain.
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.
PMID: 18287535 [PubMed - in process]
PMCID: PMC2366852 [Available on 06/28/08] |
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