Transcriptional Regulation of Neuronal Genes and Its Effect on Neural Functions:Expression and Function of Forkhead Transcription Factors in Neurons

Journal of Pharmacological Sciences

Kohji Fukunaga²  Takao Ishigami²  Takayuki Kawano¹ 

[1] Department of Neurosurgery, Kumamoto University School of Medicine;Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University

关键词: forkhead transcription factor;    brain ischemia;    Fas ligand;    Bim;    delayed neuronal death;   

DOI  :  10.1254/jphs.FMJ05001X3

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(46)Cited-By(40)Forkhead box transcription factor, class O (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 AFX, FKHRL1, and FKHR. FKHR is phosphorylated on three sites (Thr-24, Ser-256, and Ser-319) in a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner, thereby inhibiting death signals. We here documented dephosphorylation of FKHR following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in gerbil and mouse brains. The activation of FKHR preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FKHR activation was accompanied by an increase in DNA binding activity for FKHR-responsive element on the Fas ligand promoter. We also defined FKHR-induced downstream targets such as Fas ligand and Bim in brain ischemia. Therefore, we propose a new strategy to rescue neurons from delayed neuronal death by promoting the survival signaling. Sodium orthovanadate, a protein tyrosine phosphatase inhibitor, up-regulated Akt activity in the brain and in turn rescue neurons from delayed neuronal death by inhibiting FKHR-dependent or -independent death signals in neurons.

【 授权许可】

Unknown