FOXO3a is activated in response to hypoxic stress and inhibits HiF1-induced apoptosis via regulation of CITED2
FOXO3a is activated in response to hypoxic stress and inhibits HiF1-induced apoptosis via regulation of CITED2
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DOI：
10.1016/j.molcel.2007.10.035
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发表时间：
2007-12-28
期刊：
影响因子：
16
通讯作者：
Mak, Tak W.
中科院分区：
文献类型：
--
作者：
Bakker, Walbert J.;Harris, Isaac S.;Mak, Tak W.
FOXO转录因子是响应于各种应激刺激的细胞存活的重要调节因子，其中包括氧化应激、DNA损伤和营养剥夺。在这里，我们报告的作用FOXO 3a缺氧应激条件下。响应于缺氧，FOXO3a转录水平以HIF 1依赖性方式积累，导致IFO3a活性增强。我们发现，转录CITED 2，转录辅因子，在负反馈回路中的功能，以控制HIF 1活性，是由FOXO 3a在缺氧诱导。在成纤维细胞以及乳腺癌细胞中，FOXO 3a通过刺激CITED 2的转录来抑制HR诱导的细胞凋亡，这导致促细胞凋亡HIP靶基因NIX和RTP 801的表达减少。因此，通过微调HIF 1活性，FOXO 3a在正常细胞和癌细胞对缺氧应激的存活反应中起着重要作用。
FOXO transcription factors are important regulators of cell survival in response to a variety of stress stimuli, among which are oxidative stress, DNA damage, and nutrient deprivation. Here we report a role for FOXO3a under conditions of hypoxic stress. In response to hypoxia, FOXO3a transcript levels accumulate in an HIF1-dependent way, resulting in enhanced IFOXO3a activity. We show that transcription of CITED2, a transcriptional cofactor that functions in a negative feedback loop to control HIF1 activity, is induced by FOXO3a during hypoxia. In fibroblasts as well as in breast cancer cells, FOXO3a inhibits HIR-induced apoptosis by stimulating the transcription of CITED2, which results in reduced expression of the proapoptotic HIP target genes NIX and RTP801. Thus, by fine-tuning HIF1 activity, FOXO3a plays an important role in the survival response of normal and cancer cells in response to hypoxic stress.