Cited by 2,476Cancer, Hypoxia, and MetabolismDevelopmental Biology and Gene RegulationAngiogenesis and VEGF in Cancer

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Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α

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Iyer, Narayan V., Kotch, Lori E., Agani, Faton, Leung, Sandra W., Laughner, Erik, Wenger, Roland H., Gassmann, Max, Gearhart, John D., Lawler, Ann M., Yu, Aimee Y., Semenza, Gregg L.·1998·Genes & Development

DOI 10.1101/gad.12.2.149PMC PMC316445

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Abstract

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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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.
ORCID: Iyer, Narayan V.
Wenger, Roland H.
Gassmann, Max
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
DOI: 10.1101/gad.12.2.149
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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Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α

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