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. 2007 Dec 28;28(6):941-53.
doi: 10.1016/j.molcel.2007.10.035.

FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2

Walbert J Bakker  1 , Isaac S Harris, Tak W Mak
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Free article

FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2

Walbert J Bakker et al. Mol Cell. .
Free article

Abstract

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.

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