FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function
Identifieur interne : 000355 ( Main/Exploration ); précédent : 000354; suivant : 000356FoxO3A promotes metabolic adaptation to hypoxia by antagonizing Myc function
Auteurs : Kim Steen Jensen [Danemark] ; Tina Binderup [Danemark] ; Klaus Thorleif Jensen [Danemark] ; Ib Therkelsen [Danemark] ; Rehannah Borup [Danemark] ; Elise Nilsson [Suède] ; Hinke Multhaupt [Danemark] ; Caroline Bouchard [Allemagne] ; Bj Rn Quistorff [Danemark] ; Andreas Kj R [Danemark] ; Göran Landberg [Suède, Royaume-Uni] ; Peter Staller [Danemark]Source :
- The EMBO Journal [ 0261-4189 ] ; 2011-11-16.
English descriptors
- Teeft :
- Aco2, Actin, Apoptosis, Biol, Biol chem, Biology organization, Biology organization foxo3a, Caspase, Cell biol, Cell clones, Cell death, Cell survival, Clone, Control hypoxic metabolism, Ctrl, Downregulate, Embo, Embo journal, Error bars, Fhre, Foxo, Foxo factors, Foxo3a, Foxo3a knockdown cell clones, Foxo3a knockdown cells, Gene, Glucose, Glucose uptake, Glycolytic, Hela, Hela cells, Hela ctrl, Hypoxia, Hypoxic, Hypoxic repression, Immunoblotting, Independent experiments, Knockdown, Lars2, Lower panel, Metabolic adaptation, Metabolism, Mitochondrial, Mitochondrial biogenesis, Mitochondrial genes, Mitochondrial mass, Mrna, Mrna levels, Normoxia, Oxnad1, Oxygen consumption, Probe sets, Promoter, Protein levels, Qpcr, Sirna, Subunit, Supplementary figure, Supplementary table, Target genes, Transcription, Transcriptional, Transfected, Tumour, U2os, U2os cell clones, Xenograft, Xenograft tumours, Zhang.
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.
This paper characterizes FoxO3A as required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production. Mechanistically, FoxO3A is shown to promote hypoxic cell survival by directly antagonizing c‐Myc at nuclear encoded mitochondrial genes.
Url:
DOI: 10.1038/emboj.2011.323
Affiliations:
- Allemagne, Danemark, Royaume-Uni, Suède
- Angleterre, District de Giessen, Grand Manchester, Hesse (Land), Hovedstaden
- Copenhague, Manchester, Marbourg
- Université de Manchester
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type="city">Copenhague</settlement><region type="région" nuts="2">Hovedstaden</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Danemark</country></affiliation></author></analytic><monogr></monogr><series><title level="j">The EMBO Journal</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2011-11-16">2011-11-16</date><biblScope unit="volume">30</biblScope><biblScope unit="issue">22</biblScope><biblScope unit="page" from="4554">4554</biblScope><biblScope unit="page" to="4570">4570</biblScope></imprint><idno type="ISSN">0261-4189</idno></series><idno type="istex">8914E35786B08AB7269327A98613F0D81C65DF9D</idno><idno type="DOI">10.1038/emboj.2011.323</idno><idno type="ArticleID">EMBJ2011323</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0261-4189</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Aco2</term><term>Actin</term><term>Apoptosis</term><term>Biol</term><term>Biol chem</term><term>Biology organization</term><term>Biology organization foxo3a</term><term>Caspase</term><term>Cell biol</term><term>Cell clones</term><term>Cell death</term><term>Cell survival</term><term>Clone</term><term>Control hypoxic metabolism</term><term>Ctrl</term><term>Downregulate</term><term>Embo</term><term>Embo journal</term><term>Error bars</term><term>Fhre</term><term>Foxo</term><term>Foxo factors</term><term>Foxo3a</term><term>Foxo3a knockdown cell clones</term><term>Foxo3a knockdown cells</term><term>Gene</term><term>Glucose</term><term>Glucose uptake</term><term>Glycolytic</term><term>Hela</term><term>Hela cells</term><term>Hela ctrl</term><term>Hypoxia</term><term>Hypoxic</term><term>Hypoxic repression</term><term>Immunoblotting</term><term>Independent experiments</term><term>Knockdown</term><term>Lars2</term><term>Lower panel</term><term>Metabolic adaptation</term><term>Metabolism</term><term>Mitochondrial</term><term>Mitochondrial biogenesis</term><term>Mitochondrial genes</term><term>Mitochondrial mass</term><term>Mrna</term><term>Mrna levels</term><term>Normoxia</term><term>Oxnad1</term><term>Oxygen consumption</term><term>Probe sets</term><term>Promoter</term><term>Protein levels</term><term>Qpcr</term><term>Sirna</term><term>Subunit</term><term>Supplementary figure</term><term>Supplementary table</term><term>Target genes</term><term>Transcription</term><term>Transcriptional</term><term>Transfected</term><term>Tumour</term><term>U2os</term><term>U2os cell clones</term><term>Xenograft</term><term>Xenograft tumours</term><term>Zhang</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="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.</div><div type="abstract">This paper characterizes FoxO3A as required for hypoxic suppression of mitochondrial mass, oxygen consumption, and ROS production. Mechanistically, FoxO3A is shown to promote hypoxic cell survival by directly antagonizing c‐Myc at nuclear encoded mitochondrial genes.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Danemark</li><li>Royaume-Uni</li><li>Suède</li></country><region><li>Angleterre</li><li>District de Giessen</li><li>Grand Manchester</li><li>Hesse (Land)</li><li>Hovedstaden</li></region><settlement><li>Copenhague</li><li>Manchester</li><li>Marbourg</li></settlement><orgName><li>Université de Manchester</li></orgName></list><tree><country name="Danemark"><region name="Hovedstaden"><name sortKey="Jensen, Kim Steen" sort="Jensen, Kim Steen" uniqKey="Jensen K" first="Kim Steen" last="Jensen">Kim Steen Jensen</name></region><name sortKey="Binderup, Tina" sort="Binderup, Tina" uniqKey="Binderup T" first="Tina" last="Binderup">Tina Binderup</name><name sortKey="Binderup, Tina" sort="Binderup, Tina" uniqKey="Binderup T" first="Tina" last="Binderup">Tina Binderup</name><name sortKey="Borup, Rehannah" sort="Borup, Rehannah" uniqKey="Borup R" first="Rehannah" last="Borup">Rehannah Borup</name><name sortKey="Jensen, Klaus Thorleif" sort="Jensen, Klaus Thorleif" uniqKey="Jensen K" first="Klaus Thorleif" last="Jensen">Klaus Thorleif Jensen</name><name sortKey="Kj R, Andreas" sort="Kj R, Andreas" uniqKey="Kj R A" first="Andreas" last="Kj R">Andreas Kj R</name><name sortKey="Kj R, Andreas" sort="Kj R, Andreas" uniqKey="Kj R A" first="Andreas" last="Kj R">Andreas Kj R</name><name sortKey="Multhaupt, Hinke" sort="Multhaupt, Hinke" uniqKey="Multhaupt H" first="Hinke" last="Multhaupt">Hinke Multhaupt</name><name sortKey="Quistorff, Bj Rn" sort="Quistorff, Bj Rn" uniqKey="Quistorff B" first="Bj Rn" last="Quistorff">Bj Rn Quistorff</name><name sortKey="Staller, Peter" sort="Staller, Peter" uniqKey="Staller P" first="Peter" last="Staller">Peter Staller</name><name sortKey="Staller, Peter" sort="Staller, Peter" uniqKey="Staller P" first="Peter" last="Staller">Peter Staller</name><name sortKey="Therkelsen, Ib" sort="Therkelsen, Ib" uniqKey="Therkelsen I" first="Ib" last="Therkelsen">Ib Therkelsen</name></country><country name="Suède"><noRegion><name sortKey="Nilsson, Elise" sort="Nilsson, Elise" uniqKey="Nilsson E" first="Elise" last="Nilsson">Elise Nilsson</name></noRegion><name sortKey="Landberg, Goran" sort="Landberg, Goran" uniqKey="Landberg G" first="Göran" last="Landberg">Göran Landberg</name></country><country name="Allemagne"><region name="Hesse (Land)"><name sortKey="Bouchard, Caroline" sort="Bouchard, Caroline" uniqKey="Bouchard C" first="Caroline" last="Bouchard">Caroline Bouchard</name></region></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Landberg, Goran" sort="Landberg, Goran" uniqKey="Landberg G" first="Göran" last="Landberg">Göran Landberg</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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