Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL)
Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL)
复制标题
叉头转录因子 3a (FOXO3a) 通过上调 von Hippel-Lindau 基因 (VHL) 调节缺氧信号
DOI：
10.1074/jbc.m116.745471
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发表时间：
2016-12-02
影响因子：
4.8
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
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作者：
Liu, Xing;Cai, Xiaolian;Xiao, Wuhan
FOXO 3a是FOXO家族转录因子的一员，在DNA损伤、热量限制和氧化应激时调节细胞存活。von Hippel-Lindau（VHL）肿瘤抑制基因编码E3泛素连接酶复合物的一个组分，该复合物在有氧条件下介导缺氧诱导因子的降解，从而作为缺氧信号传导的关键调节因子之一。然而，FOXO 3a是否影响细胞缺氧应激仍然未知。在这里，我们表明，FOXO 3a直接结合到VHL启动子和上调VHL表达。使用斑马鱼模型，我们证实了上调vhl的foxo 3b，直系同源的哺乳动物FOXO 3a。此外，通过采用成簇规则间隔短回文重复序列（CRISPR）相关的RNA引导内切核酸酶Cas9（CRISPR/Cas9）技术，我们删除了斑马鱼中的foxo 3b，并确定缺氧诱导基因的表达受到缺氧的影响。此外，foxo 3b-null斑马鱼表现出急性缺氧耐受性受损，导致死亡。总之，我们的研究结果表明，通过调节低氧诱导因子的活性，通过上调VHL，FOXO 3a（foxo 3b）在生存中起着重要的作用，在应对缺氧应激。
FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown. Here we show that FOXO3a directly binds to the VHL promoter and up-regulates VHL expression. Using a zebrafish model, we confirmed the up-regulation of vhl by foxo3b, an ortholog of mammalian FOXO3a. Furthermore, by employing the clustered regularly interspaced short palindromic repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (CRISPR/Cas9) technology, we deleted foxo3b in zebrafish and determined that expression of hypoxia-inducible genes was affected under hypoxia. Moreover, foxo3b-null zebrafish exhibited impaired acute hypoxic tolerance, resulting in death. In conclusion, our findings suggest that, by modulating hypoxia-inducible factor activity via up-regulation of VHL, FOXO3a (foxo3b) plays an important role in survival in response to hypoxic stress.