The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Abstract
The hypoxia-inducible factors (HIFs) 1α and 2α are key mammalian transcription factors that exhibit dramatic increases in both protein stability and intrinsic transcriptional potency during low-oxygen stress. This increased stability is due to the absence of proline hydroxylation, which in normoxia promotes binding of HIF to the von Hippel–Lindau (VHL tumor suppressor) ubiquitin ligase. We now show that hypoxic induction of the COOH-terminal transactivation domain (CAD) of HIF occurs through abrogation of hydroxylation of a conserved asparagine in the CAD. Inhibitors of Fe(II)- and 2-oxoglutarate–dependent dioxygenases prevented hydroxylation of the Asn, thus allowing the CAD to interact with the p300 transcription coactivator. Replacement of the conserved Asn by Ala resulted in constitutive p300 interaction and strong transcriptional activity. Full induction of HIF-1α and -2α, therefore, relies on the abrogation of both Pro and Asn hydroxylation, which during normoxia occur at the degradation and COOH-terminal transactivation domains, respectively.
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In the citing paper
“It was recently shown that HIFα association with p300 is blocked under normoxic conditions by hydroxylation of a conserved asparagine residue within the CAD (Lando et al. 2002).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Lando et al. 2002
In the citing paper
“As with HIF prolyl hydroxylases, endogenous HIF asparaginyl hydroxylase activity can be blocked with competitive inhibitors of 2-oxoglutarate and with iron chelators (Lando et al. 2002), suggesting that this enzyme might also resemble known hydroxylase enzymes.”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Lando et al. 2002
In the citing paper
“HIF transcriptional activity is suppressed under normoxic conditions by hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators.”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Lando et al. 2002
In the citing paper
“Full induction of the hypoxic response pathway upon exposure to low oxygen levels requires both stabilization of the HIFα transcription factor and activation of the CAD (Lando et al. 2002).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Lando et al. 2002
In the citing paper
“Asparagine hydroxylation is abrogated by hypoxia, allowing HIF to recruit the larger transcriptional apparatus to hypoxiaresponsive target genes (Lando et al. 2002).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Lando et al. 2002
In the citing paper
“This mechanism attenuates HIF transcriptional activity during early reoxygenation, acting as a buffer that limits the excessive metabolic activation and oxidative stress during the transition from hypoxia to normoxia”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [53]
In the citing paper
“FIH-1 functions at lower oxygen tensions than PHDs and hydroxylates a single asparagine residue within the C-terminal transactivation domain of HIF-1α, consequently limiting engagement of transcriptional co-activator complexes [52,53]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [53]
In the citing paper
“Hif-1α is also hydroxylated in an oxygen-dependent reaction on a highly conserved asparagine residue by FIH-1 (Factor inhibiting HIF-1), which blocks the ability of Hif-1α to recruit transcriptional coactivators such as p300/CBP, in turn limiting transcriptional activation by Hif-1α under non-hypoxic conditions [45, 46].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [46]
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Metadata
- Authors
- Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L.
- Affiliations
- Adelaide University (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- Corresponding author
- Whitelaw, Murray L.
- Venue
- Science
- Published
- 2002-02
- Volume
- 295
- Issue
- 5556
- Pages
- 858-861
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1973092951
- Semantic Scholar
- 56986a3761858ed94221534104f97dacadfc3a98
- Cited by
- 1,558
- References
- 28
- Citations by year
- 2026: 25 · 2025: 31 · 2024: 34 · 2023: 46 · 2022: 46 · 2021: 48 · 2020: 43 · 2019: 50 · 2018: 50 · 2017: 48 · 2016: 58 · 2015: 58 · 2014: 58 · 2013: 67 · 2012: 58
- FWCI
- 49.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia-inducible factor, HIF-1α, HIF-2α, proline hydroxylation, transactivation domain, p300 coactivator, protein stability, 2-oxoglutarate-dependent dioxygenase, transcriptional activation, hypoxia
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Amino Acid Sequence, Animals, Asparagine, Cell Line, Humans, Mixed Function Oxygenases, Hydroxylation, Molecular Sequence Data, Mutation, Oxygen, Proline, Recombinant Fusion Proteins, Mass Spectrometry, Transcription Factors, Transcriptional Activation, Trans-Activators, Cell Hypoxia, Protein Structure, Tertiary, Amino Acid Substitution, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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