Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Abstract
As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
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Vascularization is severely impaired in HIF1A-/- and HIF2A-/- mice.
“Vascularization is severely impaired in HIF1A -/- (Carmeliet et al., 1998;Ryan et al., 1998) and HIF2A -/- (Peng et al., 2000) mice.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Carmeliet et al., 1998
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Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer
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Hypoxia: a Double-Edged Sword in Cancer Therapy
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HIF2α cooperates with RAS to promote lung tumorigenesis in mice
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- Authors
- Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., Koch, C. J., Ratcliffe, P., Moons, L., Jain, R. K., Collen, D., & Keshet, E.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Hebrew University of Jerusalem (IL)
- Sanofi (France) (FR)
- Harvard University (US)
- Weizmann Institute of Science (IL)
- Centre for Human Genetics (GB)
- University of Pennsylvania (US)
- Corresponding author
- Carmeliet, Peter
- ORCID
- Venue
- Nature
- Published
- 1998-07-30
- Volume
- 394
- Issue
- 6692
- Pages
- 485-490
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1578283200
- Cited by
- 2,502
- References
- 2
- Citations by year
- 2026: 37 · 2025: 41 · 2024: 54 · 2023: 59 · 2022: 78 · 2021: 100 · 2020: 67 · 2019: 57 · 2018: 59 · 2017: 78 · 2016: 90 · 2015: 86 · 2014: 105 · 2013: 102 · 2012: 83
- FWCI
- 38.21
- Type
- journal article
- Language
- en
- Update notices
- erratum (1998-10-01)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- HIF-1α, hypoxia, apoptosis, cell proliferation, tumor angiogenesis, hypoglycemia, embryonic stem cells, vascular endothelial growth factor, p53, p21, Bcl-2, p27, GADD153, cell cycle regulation, tumor hypoxia, oxygen homeostasis
- MeSH terms
- Animals, Cell Division, Cell Line, DNA-Binding Proteins, Glucose, Cricetinae, Lymphokines, Mice, Nude, Neoplasms, Experimental, Neovascularization, Pathologic, Nuclear Proteins, Oxygen, Regional Blood Flow, Stem Cells, Transcription Factors, Cell Hypoxia, Endothelial Growth Factors, CHO Cells, Apoptosis, Gene Targeting, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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