Cited by 2,617Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismGenomics and Chromatin Dynamics

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A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation

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Semenza, G L, Wang, G L·1992·Molecular and Cellular Biology

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Abstract

We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.

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Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene.
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Authors: Semenza, G. L., & Wang, G. L.
Affiliations: Johns Hopkins University (US)
ORCID: Semenza, G L
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1992-12
Volume: 12
Issue: 12
Pages: 5447-5454
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.12.12.5447
PMC: PMC360482
OpenAlex: W2135836641
Cited by: 2,617
References: 1
Citations by year: 2026: 15 · 2025: 49 · 2024: 72 · 2023: 97 · 2022: 119 · 2021: 129 · 2020: 120 · 2019: 96 · 2018: 91 · 2017: 99 · 2016: 97 · 2015: 111 · 2014: 107 · 2013: 112 · 2012: 104
FWCI: 10.74
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01dk039869-16)
National Institute of Diabetes and Digestive and Kidney Diseases (DK 39869)
Topics: Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: erythropoietin gene, transcriptional activation, hypoxia response, de novo protein synthesis, nuclear factor binding, 3' flanking region, enhancer function, cycloheximide sensitivity, DNase I footprinting, mutagenesis
MeSH terms: Base Sequence, Binding Sites, Cell Line, Deoxyribonuclease I, DNA, Enhancer Elements, Genetic, Erythropoietin, Gene Expression Regulation, Humans, Molecular Sequence Data, Oxygen, Transcription Factors, Transcription, Genetic, Cell Hypoxia

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A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation

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