FOXO3a Is Activated in Response to Hypoxic Stress and Inhibits HIF1-Induced Apoptosis via Regulation of CITED2
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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.
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FOXO3a regulates expression of HIF-1α transcriptional inhibitor CITED2.
“Previous reports have demonstrated that the increase in ROS in the absence of SirT3 inhibits FOXO3a activity (Sundaresan et al., 2009) and FOXO3a regulates expression of the HIF-1α transcriptional inhibitor CITED2 (Bakker et al., 2007), thus it is possible that CITED2 may have a role in our results.”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Bakker et al., 2007
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- Authors
- Bakker, W. J., Harris, I. S., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Mak, Tak W.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 28
- Issue
- 6
- Pages
- 941-953
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2035991083
- Cited by
- 277
- References
- 62
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 7 · 2023: 10 · 2022: 10 · 2021: 18 · 2020: 12 · 2019: 19 · 2018: 13 · 2017: 15 · 2016: 15 · 2015: 15 · 2014: 14 · 2013: 22 · 2012: 17
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johnson and Johnson
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- FOXO3, hypoxia, HIF-1, CITED2, apoptosis, transcriptional cofactors, negative feedback loop, Nix, RTP801, breast cancer cells, fibroblasts, cell survival, transcriptional regulation
- MeSH terms
- Forkhead Box Protein O3, Phosphoinositide-3 Kinase Inhibitors, Animals, Binding Sites, Cell Line, Cell Survival, Chromones, DNA-Binding Proteins, Fibroblasts, Flow Cytometry, Gene Expression Regulation, Humans, Models, Biological, Morpholines, Mutation, Repressor Proteins, RNA, Messenger, Transfection, Blotting, Western, Trans-Activators, Cell Hypoxia, Apoptosis, RNA, Small Interfering, NIH 3T3 Cells, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, Forkhead Transcription Factors, Embryonic Stem Cells
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