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

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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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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: Jiang, Bing-Hua
Chin, Beek Yoke
Iyer, Narayan V.
Semenza, Gregg L.
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: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8652 d)
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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Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia

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