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Cited by 782Heme Oxygenase-1 and Carbon MonoxideCancer, Hypoxia, and MetabolismHemoglobin structure and function

Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia

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Lee, Patty J., Jiang, Bing-Hua, Chin, Beek Yoke, Iyer, Narayan V., Alam, Jawed, Semenza, Gregg L., Choi, AugustineM.K.·1997·Journal of Biological Chemistry
DOI 10.1074/jbc.272.9.5375
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Abstract

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, TFR1, ceruloplasmin, and heme-oxygenase-1.

    “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]

  • Other bona fide HIF-regulated genes involved in iron metabolism include transferrin, TFR1, ceruloplasmin, and heme-oxygenase-1.

    “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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Research works printed but not linked: 9

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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
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1997-02
Volume
272
Issue
9
Pages
5375-5381
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.272.9.5375
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
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 › Cell Biology › 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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