The Roles of Cdk5-Mediated Subcellular Localization of FOXO1 in Neuronal Death
The Roles of Cdk5-Mediated Subcellular Localization of FOXO1 in Neuronal Death
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Cdk5 介导的 FOXO1 亚细胞定位在神经元死亡中的作用
DOI：
10.1523/jneurosci.3051-14.2015
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发表时间：
2015-02
影响因子：
5.3
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Yun-Wu;Bu, Guojun;Xu, Huaxi;Zhang, Jie
细胞周期蛋白依赖性激酶5（Cdk 5）的缺乏与脑发育过程中有丝分裂后皮质神经元的死亡有关。我们现在报告，在小鼠皮层神经元，Cdk 5能够磷酸化的转录因子FOXO 1在Ser 249在体外和体内。由H2 O2或β-淀粉样蛋白引起的细胞外刺激引起的细胞应激促进Cdk 5、FOXO 1核输出的超活化和其下游转录活性的抑制。相反，Cdk 5的丢失导致FOXO 1易位到细胞核中：由于AKT活性降低而独立于S249磷酸化的转变。核FOXO 1上调促凋亡基因BIM的转录，导致神经元死亡，当内源性FOXO 1被细胞质定位形式的FOXO 1 FOXO 1-S249 D取代时，可以挽救神经元死亡。Cdk 5通过抑制FOXO 1转录活性和BIM表达在细胞质而非细胞核中减弱神经元死亡。总之，我们的研究结果表明，Cdk 5起着一个新的和意想不到的作用，在有丝分裂后神经元的退化，通过调制的细胞位置FOXO 1，这构成了一个替代途径，通过Cdk 5缺陷导致神经元死亡。
Deficiency of cyclin-dependent kinase 5 (Cdk5) has been linked to the death of postmitotic cortical neurons during brain development. We now report that, in mouse cortical neurons, Cdk5 is capable of phosphorylating the transcription factor FOXO1 at Ser249 in vitro and in vivo. Cellular stresses resulting from extracellular stimulation by H2O2 or β-amyloid promote hyperactivation of Cdk5, FOXO1 nuclear export and inhibition of its downstream transcriptional activity. In contrast, a loss of Cdk5 leads to FOXO1 translocation into the nucleus: a shift due to decreased AKT activity but independent of S249 phosphorylation. Nuclear FOXO1 upregulates transcription of the proapoptotic gene, BIM, leading to neuronal death, which can be rescued when endogenous FOXO1 was replaced by the cytoplasmically localized form of FOXO1, FOXO1-S249D. Cytoplasmic, but not nuclear, Cdk5 attenuates neuronal death by inhibiting FOXO1 transcriptional activity and BIM expression. Together, our findings suggest that Cdk5 plays a novel and unexpected role in the degeneration of postmitotic neurons through modulation of the cellular location of FOXO1, which constitutes an alternative pathway through which Cdk5 deficiency leads to neuronal death.
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影响因子：
4.8
作者：
Yuan, Zengqiang;Lehtinen, Maria K.;Bonni, Azad
通讯作者：
Bonni, Azad
影响因子：
9.8
作者：
Jessberger S;Aigner S;Clemenson GD Jr;Toni N;Lie DC;Karalay O;Overall R;Kempermann G;Gage FH
通讯作者：
Gage FH
DOI：
10.1073/pnas.89.22.10867
发表时间：
1992-11-15
影响因子：
11.1
作者：
HELLMICH, MR;PANT, HC;BATTEY, JF
通讯作者：
BATTEY, JF
影响因子：
4.3
作者：
Jie Zhang;K. Herrup
通讯作者：
Jie Zhang;K. Herrup
影响因子：
64.8
作者：
TSAI, LH;DELALLE, I;HARLOW, E
通讯作者：
HARLOW, E