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FoxO3A promotes met...
FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function
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Jensen, Kim Steen (author)
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Binderup, Tina (author)
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Jensen, Klaus Thorleif (author)
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Therkelsen, Ib (author)
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Borup, Rehannah (author)
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Nilsson, Elise (author)
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Multhaupt, Hinke (author)
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Bouchard, Caroline (author)
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Quistorff, Bjorn (author)
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Kjaer, Andreas (author)
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- Landberg, Göran (author)
- Lund University,Lunds universitet,Patologi, Malmö,Forskargrupper vid Lunds universitet,Pathology, Malmö,Lund University Research Groups
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Staller, Peter (author)
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(creator_code:org_t)
- 2011-09-13
- 2011
- English.
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In: EMBO Journal. - : Wiley. - 1460-2075 .- 0261-4189. ; 30:22, s. 4554-4570
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Abstract
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- 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
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- FoxO3A
- hypoxia
- metabolism
- mitochondrion
- Myc
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Jensen, Kim Stee ...
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Binderup, Tina
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Jensen, Klaus Th ...
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Therkelsen, Ib
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Borup, Rehannah
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Nilsson, Elise
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show more...
-
Multhaupt, Hinke
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Bouchard, Caroli ...
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Quistorff, Bjorn
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Kjaer, Andreas
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Landberg, Göran
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Staller, Peter
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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EMBO Journal
- By the university
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Lund University