FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

Kim Steen Jensen, Tina Binderup, Klaus Thorleif Jensen, Ib Therkelsen, Rehannah Borup, Elise Nilsson, Hinke Arnolda B V H Multhaupt, Caroline Bouchard, Bjørn Quistorff, Andreas Kjaer, Göran Landberg, Peter Staller

99 Citationer (Scopus)

Abstract

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.
OriginalsprogEngelsk
TidsskriftE M B O Journal
Vol/bind30
Udgave nummer22
Sider (fra-til)4554-70
Antal sider17
ISSN0261-4189
DOI
StatusUdgivet - 2011

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