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A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

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Title A feed-forward loop involving Trib3, Akt and FoxO
mediates death of NGF-deprived neurons
 
Creator Zareen, N
Biswas, SC
Greene, LA
 
Subject Cell Biology & Physiology
 
Description The mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required
for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/ activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron death
 
Publisher Nature Publishing Group
 
Date 2013
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2404/1/Cell_Death_and_Differentiation_(2013)_20%2C_1719%E2%80%931730.pdf
Zareen, N and Biswas, SC and Greene, LA (2013) A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons. Cell Death and Differentiation, 20. pp. 1719-1730.
 
Relation http://www.eprints.iicb.res.in/2404/