Type

Journal Article

Authors

J H M Prehn
H J Huber
C G Concannon
H Düssmann
P Weisová
H Bonner
N M C Connolly
D Davila

Subjects

Biochemistry

Topics
proto oncogene proteins c akt tor serine threonine kinases foxo3 protein mouse proto oncogene proteins cytology down regulation amp activated protein kinases transcription factor ap 1 cell nucleus signal transduction genetics rna small interfering metabolism rna interference neurons bcl 2 like protein 11 membrane proteins forkhead transcription factors phosphorylation rats apoptosis regulatory proteins antagonists inhibitors glucose animals apoptosis mice cells cultured promoter regions genetic

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 pro-apoptotic 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 feed-forward 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 -> PubMed

Full list of authors on original publication

J H M Prehn, H J Huber, C G Concannon, H Düssmann, P Weisová, H Bonner, N M C Connolly, D 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
Helena P Bonner
Royal College of Surgeons in Ireland
Total Publications: 15
 
6
Niamh M C Connolly
Royal College of Surgeons in Ireland
Total Publications: 14