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Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia
Open accessAbstract
Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O2, and this induction was dependent on gene transcription. Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5'-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1). A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1alpha and HIF-1beta protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity. Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response.
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“Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, which transports serum iron in its ferric form (Fe3+), its high affinity receptor TFR1, 183–185 ceruloplasmin, which oxidizes Fe2+ to Fe3+ and is important for iron transport, 186 and heme-oxygenase-1, which is critical for the recycling of iron from phagocytosed erythrocytes.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [186]
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“Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, which transports serum iron in its ferric form (Fe3+), its high affinity receptor TFR1, 183–185 ceruloplasmin, which oxidizes Fe2+ to Fe3+ and is important for iron transport, 186 and heme-oxygenase-1, which is critical for the recycling of iron from phagocytosed erythrocytes.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [187]
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Metadata
- Authors
- Lee, P. J., Jiang, B.-H., Chin, B. Y., Iyer, N. V., Alam, J., Semenza, G. L., & Choi, A. K.
- Affiliations
- Johns Hopkins University (US)
- Ochsner Medical Center (US)
- Corresponding author
- Alam, Jawed
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-02
- Volume
- 272
- Issue
- 9
- Pages
- 5375-5381
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2081635255
- Cited by
- 782
- References
- 50
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 26 · 2023: 17 · 2022: 22 · 2021: 27 · 2020: 31 · 2019: 21 · 2018: 14 · 2017: 17 · 2016: 19 · 2015: 16 · 2014: 18 · 2013: 28 · 2012: 21
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5k11ag000516-03, 5r01dk043135-07)
- National Institute on Aging
- National Heart, Lung, and Blood Institute (R01HL055338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- HIF-1, heme oxygenase-1, hypoxia, transcriptional activation, vascular smooth muscle cells, HIF-1α, ARNT, promoter regulation, hepatoma cells, oxygen deprivation
- MeSH terms
- Animals, Hypoxia, Base Sequence, Dactinomycin, DNA-Binding Proteins, Heme Oxygenase (Decyclizing), Molecular Sequence Data, Muscle, Smooth, Vascular, Nuclear Proteins, RNA, Messenger, Transcription Factors, Restriction Mapping, Transcriptional Activation, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, Helix-Loop-Helix Motifs, Mice, Rats, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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