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Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
Open accessAbstract
Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia-inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1a −/− embryonic stem cells that did not express the O 2 -regulated HIF-1α subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1a −/− embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1α resulted in developmental arrest and lethality by E11 of Hif1a −/− embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a +/+ embryos, HIF-1α expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a −/− embryos. These results demonstrate that HIF-1α is a master regulator of cellular and developmental O 2 homeostasis.
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“Hypoxia promotes aerobic glycolysis by increasing both glucose uptake and expression of glycolytic enzymes (Iyer et al., 1998).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Iyer et al., 1998
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“Most glycolytic enzymes are transcriptionally regulated by the hypoxia-inducible transcriptional factor HIF-1a (40).”
From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [40]
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“Interestingly, PGM and GPI were the only exceptions noted in a study of 15 glucose transporter and glycolytic genes in HIF1a null embryonic stem cells (40).”
From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [40]
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Metadata
- Authors
- Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-01-15
- Volume
- 12
- Issue
- 2
- Pages
- 149-162
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316445
- OpenAlex
- W2098972920
- Cited by
- 2,476
- References
- 61
- Citations by year
- 2026: 34 · 2025: 49 · 2024: 69 · 2023: 69 · 2022: 98 · 2021: 99 · 2020: 92 · 2019: 78 · 2018: 86 · 2017: 84 · 2016: 87 · 2015: 94 · 2014: 93 · 2013: 100 · 2012: 90
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institutes of Health (5r01dk039869-16)
- National Heart, Lung, and Blood Institute (R01HL55338, R01HL055338)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK39869)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypoxia-inducible factor-1α, oxygen homeostasis, hypoxia, embryonic stem cells, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, embryoid bodies, neural tube defects, cardiovascular anomalies, developmental arrest, transcriptional regulation
- MeSH terms
- Animals, Blood Vessels, Cell Division, Cells, Cultured, DNA-Binding Proteins, Embryo, Mammalian, Homeostasis, Immunohistochemistry, Lymphokines, Mice, Inbred C57BL, Nuclear Proteins, Oxygen, RNA, Messenger, Stem Cells, Time Factors, Transcription Factors, Immunoblotting, Endothelial Growth Factors, Mice, Knockout, Cell Respiration, Platelet Endothelial Cell Adhesion Molecule-1, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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