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

J Biol Chem. 1997 Feb 28;272(9):5375-81.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • DNA-Binding Proteins / pharmacology*
  • Dactinomycin / 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*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Restriction Mapping
  • Transcription Factors / pharmacology*
  • Transcriptional Activation


  • DNA-Binding Proteins
  • Hif1a protein, mouse
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • Dactinomycin
  • Heme Oxygenase (Decyclizing)

Associated data

  • GENBANK/U70472