Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia

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. Ac...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-02, Vol.272 (9), p.5375-5381
Main Authors: Lee, Patty J., Jiang, Bing-Hua, Chin, Beek Yoke, Iyer, Narayan V., Alam, Jawed, Semenza, Gregg L., Choi, AugustineM.K.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Dactinomycin - pharmacology
DNA-Binding Proteins - pharmacology
Gene Expression Regulation, Enzymologic - drug effects
Helix-Loop-Helix Motifs
Heme Oxygenase (Decyclizing) - genetics
Hypoxia - enzymology
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Molecular Sequence Data
Muscle, Smooth, Vascular - enzymology
Nuclear Proteins - pharmacology
Rats
Rats, Sprague-Dawley
Restriction Mapping
RNA, Messenger - metabolism
Transcription Factors - pharmacology
Transcriptional Activation
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Summary: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-1α and HIF-1β 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.9.5375