Pathophysiological Relevance of Forkhead Transcription Factors in Brain Ischemia

  • Kohji Fukunaga
  • Norifumi Shioda
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 665)


Forkhead box transcription factor, class0 (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamilies of forkhead transcription factors such as FOXO1 (FKHR), FOX03 (FKHRL1), FOX04 (AFX) and FOX06. All these FOXO members are expressed in the brain with different spatial patterns. FOXOI is phosphorylated on three sites (Thr-24, Ser-256 and Ser-319) in phosphatidylinositol 3-kinase (P13-K)/Akt-dependent manner, thereby inhibiting apoptosis signals. We here documented dephosphorylation of FOXO1, FOX03 and FOX04 following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in the gerbil and mouse brains. The dephosphorylation of FOXO1 following brain ischemia is in part mediated by constitutively active calcineurin in the mouse hippocampus. The activation of FOXOs preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FOXO1 activation is accompanied by an increase in DNA binding activity for FOXO1-responsive element on the Fas ligand promoter. Thus, downstream targets induced by FOXO1 include Fas ligand and Bcl-2-interacting mediator of cell death (Bim) in the brain ischemia. Accumulating evidence documented how FOXO activation is involved in the mechanisms of ischemic cell death. In this chapter, we document the activation mechanism of FOXO factors following brain ischemia and define their downstream targets underlying neuronal death. The pathophysiological relevance ofcrosstalk between FOXOs and calcineurin pathways is also discussed. Finally, we propose therapeutic perspectives to rescue neurons from delayed neuronal death by promoting the Akt signaling. Vanadium compounds, protein tyrosine phosphatase inhibitor, up-regulates Akt activity in the brain and thereby rescues neurons from delayed neuronal death by inhibiting FOXO-dependent and -independent death signals in neurons.


Neuronal Death Brain Ischemia Cereb Blood Flow Forkhead Transcription Factor Transient Middle Cerebral Artery Occlusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Landes Bioscience and Springer+Business Media 2009

Authors and Affiliations

  • Kohji Fukunaga
    • 1
  • Norifumi Shioda
    • 2
  1. 1.Department of Pharmacology Graduate School of Pharmaceutical Sciences 21th Century COE program “CRESCENDO”Tohoku UniversitySendaiJapan
  2. 2.Department of Pharmacology, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan

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