Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia

Lang, Kenneth J. D.; Kappel, Andreas; Goodall, Gregory J.

doi:10.1091/mbc.02-02-0017

Cited by 316RNA and protein synthesis mechanismsCancer, Hypoxia, and MetabolismRNA Research and Splicing

Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia

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Lang, Kenneth J. D., Kappel, Andreas, Goodall, Gregory J.·2002·Molecular Biology of the Cell

DOI 10.1091/mbc.02-02-0017PMC PMC111144

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Abstract

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.
“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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Disruption of HIF1Α translational control attenuates the HIF-dependent hypoxic response and solid tumour formation in vivoPreprint
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Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA- binding protein and a p53 family target, via mRNA translation
Cho, S.-J., Teng, I.-F., Zhang, M., Yin, T., Jung, Y.-S., & Chen, X. (2016)

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
Publisher: American Society for Cell Biology (ASCB)
Published: 2002-05
Volume: 13
Issue: 5
Pages: 1792-1801
ISSN: 1059-1524 (ISSN-L)
1939-4586
DOI: 10.1091/mbc.02-02-0017
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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Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia

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