Regulation of Neuronal Cell Death by MST1-FOXO1 Signaling
Regulation of Neuronal Cell Death by MST1-FOXO1 Signaling
复制标题
DOI：
10.1074/jbc.m900461200
复制
发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Bonni, Azad
中科院分区：
文献类型：
--
作者：
Yuan, Zengqiang;Lehtinen, Maria K.;Bonni, Azad
蛋白激酶哺乳动物不育20样激酶1（MST 1）在调节细胞死亡中起着关键作用。最近的研究表明，MST 1介导的氧化应激诱导的神经元细胞死亡的磷酸化转录因子FOXO 3的丝氨酸207，一个网站是保守的其他FOXO家族成员。在这里，我们表明，MST 1诱导的磷酸化FOXO 1在丝氨酸212，对应于FOXO 3中的丝氨酸207，破坏了FOXO 1与14-3-3蛋白的关联。因此，MST 1介导了原代大鼠小脑颗粒神经元中FOXO 1的核转位，这些神经元被剥夺了神经元活性。我们还发现，在颗粒神经元细胞死亡的生长因子和神经元活动撤出后，MST 1的要求，和MST 1诱导细胞死亡的FOXO 1依赖的方式。最后，我们表明，MST 1调节，支架蛋白Nore 1是必需的生存因子剥夺诱导的神经元死亡。总的来说，这些发现将MST 1-FOXO 1信号传导定义为生存因子剥夺诱导的神经元细胞死亡的重要联系，这对我们理解大脑发育和神经系统疾病具有重要意义。
The protein kinase mammalian Sterile 20-like kinase 1 (MST1) plays a critical role in the regulation of cell death. Recent studies suggest that MST1 mediates oxidative stress-induced neuronal cell death by phosphorylating the transcription factor FOXO3 at serine 207, a site that is conserved in other FOXO family members. Here, we show that MST1-induced phosphorylation of FOXO1 at serine 212, corresponding to serine 207 in FOXO3, disrupts the association of FOXO1 with 14-3-3 proteins. Accordingly, MST1 mediates the nuclear translocation of FOXO1 in primary rat cerebellar granule neurons that are deprived of neuronal activity. We also find a requirement for MST1 in cell death of granule neurons upon withdrawal of growth factors and neuronal activity, and MST1 induces cell death in a FOXO1-dependent manner. Finally, we show that the MST1-regulatory, scaffold protein Nore1 is required for survival factor deprivation induced neuronal death. Collectively, these findings define MST1-FOXO1 signaling as an important link survival factor deprivation-induced neuronal cell death with implications for our understanding of brain development and neurological diseases.