Type

Other / n/a

Authors

Jochen HM Prehn
Heinrich J Huber
Caoimhín G Concannon
Heiko Düssmann
Petronela Weisova
Helena Bonner
Niamh M Connolly
David Davila

Subjects

Engineering

Topics
foxo3 physiology network motifs physics energy depletion computational modeling excitotoxicity ampk bh3 only protein bim

Two step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate (2012)

Abstract Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the proapoptotic BH3 only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feedforward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK-mediated Bim expression and apoptosis during transient or physiological bioenergetic stress.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen HM Prehn, Heinrich J Huber, Caoimhín G Concannon, Heiko Düssmann, Petronela Weisova, Helena Bonner, Niamh M Connolly, David Davila

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46
 
4
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45
 
5
Petronela Weisova
Royal College of Surgeons in Ireland
Total Publications: 10
 
6
Helena P Bonner
Royal College of Surgeons in Ireland
Total Publications: 15
 
7
Niamh M C Connolly
Royal College of Surgeons in Ireland
Total Publications: 14