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FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function

Jensen, Kim Steen; Binderup, Tina; Jensen, Klaus Thorleif; Therkelsen, Ib; Borup, Rehannah; Nilsson, Elise; Multhaupt, Hinke; Bouchard, Caroline; Quistorff, Bjorn and Kjaer, Andreas, et al. (2011) In EMBO Journal 30(22). p.4554-4570
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... (More)
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 shor-thairpin 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. The EMBO Journal (2011) 30, 4554-4570. doi:10.1038/emboj.2011.323; Published online 13 September 2011 (Less)
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publication status
published
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keywords
FoxO3A, hypoxia, metabolism, mitochondrion, Myc
in
EMBO Journal
volume
30
issue
22
pages
4554 - 4570
publisher
Oxford University Press
external identifiers
  • wos:000297691500005
  • scopus:81255195809
ISSN
1460-2075
DOI
10.1038/emboj.2011.323
language
English
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yes
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1992118f-d946-420d-8dee-2558f15717e4 (old id 2291905)
date added to LUP
2012-01-11 16:39:54
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2017-09-24 03:52:24
@article{1992118f-d946-420d-8dee-2558f15717e4,
  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 shor-thairpin 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. The EMBO Journal (2011) 30, 4554-4570. doi:10.1038/emboj.2011.323; Published online 13 September 2011},
  author       = {Jensen, Kim Steen and Binderup, Tina and Jensen, Klaus Thorleif and Therkelsen, Ib and Borup, Rehannah and Nilsson, Elise and Multhaupt, Hinke and Bouchard, Caroline and Quistorff, Bjorn and Kjaer, Andreas and Landberg, Göran and Staller, Peter},
  issn         = {1460-2075},
  keyword      = {FoxO3A,hypoxia,metabolism,mitochondrion,Myc},
  language     = {eng},
  number       = {22},
  pages        = {4554--4570},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function},
  url          = {http://dx.doi.org/10.1038/emboj.2011.323},
  volume       = {30},
  year         = {2011},
}