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

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata


Field	Value

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is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn.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/