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Cited by 1,752Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentKruppel-like factors research

Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1

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Semenza, Gregg L., Jiang, Bing-Hua, Leung, Sandra W., Passantino, Rosa, Concordet, Jean-Paul, Maire, Pascal, Giallongo, Agata·1996·Journal of Biological Chemistry
DOI 10.1074/jbc.271.51.32529
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Abstract

Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix transcription factor which is expressed when mammalian cells are subjected to hypoxia and which activates transcription of genes encoding erythropoietin, vascular endothelial growth factor, and other proteins that are important for maintaining oxygen homeostasis. Previous studies have provided indirect evidence that HIF-1 also regulates transcription of genes encoding glycolytic enzymes. In this paper we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. We demonstrate that HIF-1 plays an essential role in activating transcription via these elements and show that although absolutely necessary, the presence of a HIF-1 binding site alone is not sufficient to mediate transcriptional responses to hypoxia. Analysis of hypoxia response elements in the ENO1 and Ldha gene promoters revealed that each contains two functionally-essential HIF-1 sites arranged as direct and inverted repeats, respectively. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1.

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  • Mutation of 5′-CGT-3′ to 5′-AAA-3′ at the core binding site significantly decreased hypoxia-induced FLuc activity.

    “Mutation of 5′-CGT-3′ to 5′-AAA-3′ at the core binding site, which eliminates HIF-1 binding (Semenza et al., 1996), significantly decreased hypoxia-induced FLuc activity (Figure 1E).”

    From Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1 (2011) · cites this paper as Semenza et al., 1996

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Research works printed but not linked: 4

  1. Madan, A., and Curtin, P. T. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 3928 -3932
  2. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5510 -5514
  3. Firth, J. D., Ebert, B. L., Pugh, C. W., and Ratcliffe, P. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6496 -6500
  4. Wang, G. L., and Semenza, G. L. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 4304 -4308

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Authors
Semenza, G. L., Jiang, B.-H., Leung, S. W., Passantino, R., Concordet, J.-P., Maire, P., & Giallongo, A.
Affiliations
  • Johns Hopkins University (US)
  • National Research Council (IT)
  • Institut Cochin (FR)
Corresponding author
Semenza, Gregg L.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1996-12
Volume
271
Issue
51
Pages
32529-32537
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.271.51.32529
OpenAlex
W2010394923
Cited by
1,752
References
49
Citations by year
2026: 36 · 2025: 52 · 2024: 62 · 2023: 83 · 2022: 71 · 2021: 98 · 2020: 60 · 2019: 69 · 2018: 72 · 2017: 65 · 2016: 87 · 2015: 51 · 2014: 78 · 2013: 73 · 2012: 68
FWCI
12.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by)
Funders
  • American Heart Association
  • National Institutes of Health (5r01dk039869-16)
  • National Heart, Lung, and Blood Institute (R01HL055338, HL55338)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK39869)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
Keywords
hypoxia response element, HIF-1, aldolase A, alpha-enolase, LDHA, promoter, transcriptional activation, glycolytic enzymes, direct and inverted repeats, oxygen homeostasis, hypoxia
MeSH terms
Hypoxia, Base Sequence, Cells, Cultured, DNA-Binding Proteins, Fructose-Bisphosphate Aldolase, Humans, L-Lactate Dehydrogenase, Molecular Sequence Data, Nuclear Proteins, Phosphopyruvate Hydratase, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Transcription, Genetic, Transfection, Restriction Mapping, Gene Expression Regulation, Enzymologic, Mutagenesis, Site-Directed, Helix-Loop-Helix Motifs, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

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