Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements.

Blanchard, K L; Acquaviva, A M; Galson, D L; Bunn, H F

doi:10.1128/mcb.12.12.5373

Cited by 215Erythropoietin and Anemia TreatmentGenomics and Chromatin DynamicsHemoglobin structure and function

Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements.

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Blanchard, K L, Acquaviva, A M, Galson, D L, Bunn, H F·1992·Molecular and Cellular Biology

DOI 10.1128/mcb.12.12.5373PMC PMC360475

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Abstract

Transcription of the human erythropoietin (Epo) gene is stimulated by exposure to hypoxia and/or cobalt in whole animals and in Hep3B cells. We have systematically investigated the promoter and 3' enhancer elements necessary for this induction by transient transfection of Hep3B cells. We define a promoter region of 53 bp and an enhancer region of 43 bp that confer hypoxia and cobalt inducibility. Each element gives rise to a 6- to 10-fold induction alone. In combination they produce a 50-fold induction after stimulation, similar to the 50- to 100-fold induction of the endogenous Epo gene. Two areas of DNA sequence homology are present in these regions. We demonstrate specific DNA-protein interactions in the enhancer and the ability of the promoter element to compete with these interactions in electrophoretic mobility shift assays. DNase I footprinting and methylation interference data further refine the cis-acting element in the 43-bp enhancer to a short region containing a direct repeat of a steroid/thyroid hormone receptor response element half-site separated by a 2-bp gap. Two half-site consensus sequences are also present in the 53-bp promoter. Site-specific mutation of the half-site sequences in the enhancer destroys the functional activity of the enhancer.

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Authors: Blanchard, K. L., Acquaviva, A. M., Galson, D. L., & Bunn, H. F.
Affiliations: Brigham and Women's Hospital (US)
ORCID: Bunn, H F
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1992-12
Volume: 12
Issue: 12
Pages: 5373-5385
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.12.12.5373
PMC: PMC360475
OpenAlex: W2144226840
Cited by: 215
References: 64
Citations by year: 2025: 4 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 6 · 2012: 4
FWCI: 9.40
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: Damon Runyon Cancer Research Foundation
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK041234, DK-41234)
Topics: Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords: erythropoietin gene, hypoxia, cobalt, promoter, 3' enhancer, thyroid hormone response element, transcriptional regulation, protein-DNA interactions, cis-regulatory elements, Hep3B cells
MeSH terms: Base Sequence, Binding, Competitive, Cell Line, Deoxyribonuclease I, DNA, Enhancer Elements, Genetic, Erythropoietin, Gene Expression Regulation, Humans, Methylation, Molecular Sequence Data, Organ Specificity, Oxygen, Promoter Regions, Genetic, Receptors, Steroid, Sequence Homology

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Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements.

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