Hypoxic Regulation of Lactate Dehydrogenase A
Open accessAbstract
The oxygen-regulated control system responsible for the induction of erythropoietin (Epo) by hypoxia is present in most (if not all) cells and operates on other genes, including those involved in energy metabolism. To understand the organization of cis-acting sequences that are responsible for oxygen-regulated gene expression, we have studied the 5' flanking region of the mouse gene encoding the hypoxically inducible enzyme lactate dehydrogenase A (LDH). Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences. The second domain was positioned close to the HIF-1 site, in an analogous position to one of the critical regions in the Epo 3' hypoxic enhancer. The third domain had the motif of a cAMP response element (CRE). Activation of cAMP by forskolin had no effect on the level of LDH mRNA in normoxia, but produced a magnified response to hypoxia that was dependent upon the integrity of the CRE, indicating an interaction between inducible factors binding the HIF-1 and CRE sites.
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GLUT1 is a downstream target gene of hypoxia and HIF1A.
“a downstream target gene of hypoxia and HIF1A,65”
From Single-cell transcriptomics of human-skin-equivalent organoids (2023) · cites this paper as [65]
The introductory passage (page unavailable) lists glucose transporters among genes regulated by oxygen. The paper does not identify GLUT1 in that passage or establish that it is a downstream target of HIF1A; its HIF-1 analysis concerns LDH-A and other genes. (LLM, conf=0.82)
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Single-cell transcriptomics of human-skin-equivalent organoids
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- Authors
- Firth, J. D., Ebert, B. L., & Ratcliffe, P. J.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Firth, John D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-09
- Volume
- 270
- Issue
- 36
- Pages
- 21021-21027
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2080032941
- Cited by
- 576
- References
- 0
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 25 · 2023: 17 · 2022: 19 · 2021: 18 · 2020: 21 · 2019: 13 · 2018: 12 · 2017: 11 · 2016: 27 · 2015: 11 · 2014: 12 · 2013: 13 · 2012: 19
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- 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 › Cell Biology › Hemoglobin structure and function
- Keywords
- LDHA, hypoxia, HIF-1, cAMP response element, 5'-flanking region, cis-regulatory elements, erythropoietin, PGK1, forskolin, transcriptional regulation
- MeSH terms
- Animals, Base Sequence, DNA Mutational Analysis, DNA-Binding Proteins, Erythropoietin, Colforsin, HeLa Cells, Humans, L-Lactate Dehydrogenase, Molecular Sequence Data, Nuclear Proteins, Oxygen, Regulatory Sequences, Nucleic Acid, Transcription Factors, Cell Hypoxia, Gene Expression Regulation, Enzymologic, Sequence Deletion, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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