Abstract
FOXO transcription factors are important regulators of cell survival in response to a variety of stress stimuli, among which are oxidative stress, DNA damage, and nutrient deprivation. Here we report a role for FOXO3a under conditions of hypoxic stress. In response to hypoxia, FOXO3a transcript levels accumulate in an HIF1-dependent way, resulting in enhanced FOXO3a activity. We show that transcription of CITED2, a transcriptional cofactor that functions in a negative feedback loop to control HIF1 activity, is induced by FOXO3a during hypoxia. In fibroblasts as well as in breast cancer cells, FOXO3a inhibits HIF1-induced apoptosis by stimulating the transcription of CITED2, which results in reduced expression of the proapoptotic HIF1 target genes NIX and RTP801. Thus, by fine-tuning HIF1 activity, FOXO3a plays an important role in the survival response of normal and cancer cells in response to hypoxic stress.
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Binding Sites / genetics
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Blotting, Western
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Cell Hypoxia
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Cell Line
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Cell Line, Tumor
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Cell Survival / genetics
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Cell Survival / physiology
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Chromones / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Flow Cytometry
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation / drug effects
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Humans
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / physiology*
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Mice
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Models, Biological
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Morpholines / pharmacology
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Mutation
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NIH 3T3 Cells
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transfection
Substances
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Chromones
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Cited2 protein, mouse
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DNA-Binding Proteins
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Hypoxia-Inducible Factor 1
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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Repressor Proteins
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Trans-Activators
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one