FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function.
Authors
Jensen, KBinderup, T
Jensen, K
Therkelsen, I
Borup, R
Nilsson, E
Multhaupt, H
Bouchard, C
Quistorff, B
Kjaer, A
Landberg, Göran
Staller, P
Affiliation
Biotech Research and Innovation Centre, University of Copenhagen, Denmark.Issue Date
2011-11-16
Metadata
Show full item recordAbstract
Exposure of metazoan organisms to hypoxia engages a metabolic switch orchestrated by the hypoxia-inducible factor 1 (HIF-1). HIF-1 mediates induction of glycolysis and active repression of mitochondrial respiration that reduces oxygen consumption and inhibits the production of potentially harmful reactive oxygen species (ROS). Here, we show that FoxO3A is activated in hypoxia downstream of HIF-1 and mediates the hypoxic repression of a set of nuclear-encoded mitochondrial genes. FoxO3A is required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production and promotes cell survival in hypoxia. FoxO3A is recruited to the promoters of nuclear-encoded mitochondrial genes where it directly antagonizes c-Myc function via a mechanism that does not require binding to the consensus FoxO recognition element. Furthermore, we show that FoxO3A is activated in human hypoxic tumour tissue in vivo and that FoxO3A short-hairpin RNA (shRNA)-expressing xenograft tumours are decreased in size and metabolically changed. Our findings define a novel mechanism by which FoxO3A promotes metabolic adaptation and stress resistance in hypoxia.Citation
FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function. 2011, 30 (22):4554-70 EMBO JJournal
EMBO JournalDOI
10.1038/emboj.2011.323PubMed ID
21915097Type
ArticleLanguage
enISSN
1460-2075ae974a485f413a2113503eed53cd6c53
10.1038/emboj.2011.323
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