Pathophysiological relevance of forkhead transcription factors in brain ischemia.
Pathophysiological relevance of forkhead transcription factors in brain ischemia.
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DOI：
10.1007/978-1-4419-1599-3_10
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发表时间：
2009
影响因子：
--
通讯作者：
K. Fukunaga;N. Shioda
中科院分区：
文献类型：
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作者：
K. Fukunaga;N. Shioda
叉头盒转录因子Class0(FOXO)是一种与DAF-16同源的哺乳动物转录因子，可调节秀丽线虫的寿命，包括叉头转录因子亚家族FOXO1(FKHR)、FOX03(FKHRL1)、FOX04(AFX)和FOX06。所有这些FOXO成员都以不同的空间模式在大脑中表达。FOXOI在3个位点(Thr-24、Ser-256和Ser-319)以磷脂酰肌醇3-激酶(P13-K)/Akt依赖的方式磷酸化，从而抑制细胞凋亡信号。在这里，我们记录了短暂性前脑缺血后FOXO1、FOX03和FOX04的去磷酸化及其伴随的移位到沙土鼠和小鼠脑内神经元的核内。脑缺血后FOXO1的去磷酸化在一定程度上是由小鼠海马区结构性活性的钙调神经磷酸酶介导的。在缺血性脑损伤后脆弱的海马区，FOXO的激活先于迟发性神经元死亡。FOXO1的激活伴随着Fas配体启动子上FOXO1反应元件DNA结合活性的增加。因此，FOXO1诱导的下游靶点包括Fas配体和Bcl2相互作用的细胞死亡介质(Bim)在脑缺血中。越来越多的证据证明FOXO激活是如何参与缺血性细胞死亡的机制的。在本章中，我们记录了脑缺血后FOXO因子的激活机制，并定义了它们在神经元死亡中的下游靶点。还讨论了FOXO和钙调神经磷酸酶通路之间的串扰的病理生理学相关性。最后，我们提出了通过促进Akt信号转导来挽救神经元延迟性死亡的治疗前景。蛋白酪氨酸磷酸酶抑制剂钒化合物通过抑制神经元中FOXO依赖和非依赖的死亡信号，上调脑内Akt的活性，从而使神经元免于迟发性神经元死亡。
Forkhead box transcription factor, class0 (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan ofCaenorhabditis elegansand 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.