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Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia
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HIF-1α is the regulated subunit of the HIF-1 transcription factor, which induces transcription of a number of genes involved in the cellular response to hypoxia. The HIF-1α protein is rapidly degraded in cells supplied with adequate oxygen but is stabilized in hypoxic cells. Using polysome profile analysis, we found that translation of HIF-1α mRNA in NIH3T3 cells is spared the general reduction in translation rate that occurs during hypoxia. To assess whether the 5′UTR of the HIF-1α mRNA contains an internal ribosome entry site (IRES), we constructed a dicistronic reporter with the HIF-1α 5′UTR inserted between two reporter coding regions. We found that the HIF-1α 5′UTR promoted translation of the downstream reporter, indicating the presence of an IRES. The IRES had activity comparable to that of the well-characterized c-myc IRES. IRES activity was not affected by hypoxic conditions that caused a reduction in cap-dependent translation, and IRES activity was less affected by serum-starvation than was cap-dependent translation. These data indicate that the presence of an IRES in the HIF-1α 5′UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.
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“Accumulating evidence points to the presence of an internal ribosome entry site (IRES) within HIF1A mRNA, allowing efficient translation to be maintained under hypoxic conditions [166].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [166]
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Hypoxia‐inducible factors – regulation, role and comparative aspects in tumourigenesis
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Metadata
- Authors
- Lang, K. J. D., Kappel, A., & Goodall, G. J.
- Affiliations
- South Australia Pathology (AU)
- Max Planck Society (DE)
- ORCID
- Goodall, Gregory J.
- Venue
- Molecular Biology of the Cell
- Published
- 2002-05
- Volume
- 13
- Issue
- 5
- Pages
- 1792-1801
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC111144
- OpenAlex
- W2146299409
- Cited by
- 314
- References
- 36
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 6 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 14 · 2015: 13 · 2014: 19 · 2013: 11 · 2012: 22
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Heart Foundation of Australia
- Royal Adelaide Hospital
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- hypoxia-inducible factor-1α, internal ribosome entry site, 5' untranslated region, mRNA translation, hypoxia, cap-dependent translation, serum deprivation, polysome profiling, NIH3T3 cells
- MeSH terms
- Animals, Hypoxia, HeLa Cells, Humans, Lymphokines, Oxygen, Ribosomes, RNA, Messenger, Transcription Factors, Protein Biosynthesis, Endothelial Growth Factors, Genes, myc, 3T3 Cells, Culture Media, Serum-Free, 5' Untranslated Regions, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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