FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function
| Autor: | Andreas Kjaer, Tina Binderup, Rehannah Borup, Bjørn Quistorff, Caroline Bouchard, Klaus T. Jensen, Göran Landberg, Kim Steen Jensen, Hinke A.B. Multhaupt, Ib Therkelsen, Elise Nilsson, Peter Staller |
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| Rok vydání: | 2011 |
| Předmět: |
chemistry.chemical_classification
Mitochondrial DNA Reactive oxygen species General Immunology and Microbiology General Neuroscience Hypoxia (medical) Mitochondrion Biology General Biochemistry Genetics and Molecular Biology Cell biology Small hairpin RNA chemistry RNA interference medicine Glycolysis medicine.symptom Molecular Biology Psychological repression |
| Zdroj: | The EMBO Journal. 30:4554-4570 |
| ISSN: | 0261-4189 |
| DOI: | 10.1038/emboj.2011.323 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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