General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.
Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed. The composition of the HIF-1 DNA binding complex and its isolated DNA binding subunit and the mechanism of HIF-1 activation appear to be similar or identical in EPO-producing and non-EPO-producing cells. Transcription of reporter genes containing the EPO gene enhancer is induced by hypoxia in non-EPO-producing cells and mutations that eliminate HIF-1 binding eliminate inducibility. These results provide evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia.
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
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D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008113:Liver Neoplasms; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism*; D015345:Oligonucleotide Probes; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004921:Erythropoietin; D015500:Chloramphenicol O-Acetyltransferase; D001616:beta-Galactosidase