Bakker Walbert J, Harris Isaac S, Mak Tak W
Campbell Family Institute for Breast Cancer Research, University Health Network, Ontario Cancer Institute and Princess Margaret Hospital, Toronto, ON M5G 2C1, Canada.
Mol Cell. 2007 Dec 28;28(6):941-53. doi: 10.1016/j.molcel.2007.10.035.
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 FOXO3a 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 HIF1-induced apoptosis by stimulating the transcription of CITED2, which results in reduced expression of the proapoptotic HIF1 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.
FOXO转录因子是细胞在应对多种应激刺激（包括氧化应激、DNA损伤和营养剥夺）时细胞存活的重要调节因子。在此，我们报道了FOXO3a在低氧应激条件下的作用。在低氧状态下，FOXO3a转录水平以依赖HIF1的方式积累，导致FOXO3a活性增强。我们发现，CITED2（一种在负反馈回路中发挥作用以控制HIF1活性的转录辅因子）的转录在低氧期间由FOXO3a诱导。在成纤维细胞和乳腺癌细胞中，FOXO3a通过刺激CITED2的转录来抑制HIF1诱导的细胞凋亡，这导致促凋亡HIF1靶基因NIX和RTP801的表达降低。因此，通过微调HIF1活性，FOXO3a在正常细胞和癌细胞对低氧应激的存活反应中发挥重要作用。
