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FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity
Open accessAbstract
Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O 2 -dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1α subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1α transactivation domains is also O 2 regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1α and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1α transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1α protein stabilization and transcriptional activation in response to changes in cellular O 2 concentration.
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TL;DR
The paper identifies FIH-1, a 349-amino-acid protein that binds HIF-1α and VHL and represses HIF-1 transcriptional activity. It proposes that VHL and FIH-1 act as corepressors by recruiting histone deacetylases, unifying O₂-dependent control of HIF-1α stability and transactivation.
Key findings
- A yeast two-hybrid screen of 2 × 10⁶ transformants identified FIH-1 from a 2.98-kb human brain cDNA encoding a 349-amino-acid protein; the FIH1 gene maps to chromosome 10q24 and consists of eight exons and seven introns spanning 14 kb.
- FIH-1 binds HIF-1α residues 531–826, with optimal binding requiring TAD-C; residues 757–826 are sufficient, whereas TAD-N (531–575) and TAD-C alone (786–826) did not bind.
- FIH-1 inhibits HIF-1α transactivation in 293 and Hep3B reporter assays at 1% O₂; antisense FIH-1 increases reporter expression, and FIH-1 inhibits GalA (HIF-1α 531–826) under both 20% and 1% O₂.
- FIH-1 binds VHL at a distinct site (VHL residues 1–155 sufficient for FIH-1 binding; 1–213 required for efficient HIF-1α binding), and VHL plus FIH-1 cooperatively repress GalL (HIF-1α 531–575); VHL binds HDAC-1, HDAC-2, and HDAC-3 and recruits HDACs to HIF-1α.
Methods
- Yeast two-hybrid assay using GAL4 DBD–HIF-1α(576–826) bait and a human brain cDNA prey library; 2 × 10⁶ transformants screened for histidine auxotrophy and α-galactosidase expression.
- In vitro GST pull-down assays with ³⁵S-labeled HIF-1α, FIH-1, VHL, and HDAC proteins; some GST-HIF-1α fusions were preincubated with reticulocyte lysate to induce proline hydroxylation.
- Transient transfection of HEK293 and Hep3B cells with p2.1 or pG5ElbLuc reporters and GAL4–HIF-1α fusion constructs, exposed to 20% or 1% O₂; immunoprecipitation and immunoblot assays for protein interactions.
Limitations
- Stated: coimmunoprecipitation of FIH-1 and HIF-1α was detected in cells overexpressing these proteins, so no conclusion can be drawn as to whether the interaction is regulated by cellular O₂ concentration; VHL expression may have been limiting, and no interaction of VHL with FIH-1 or HIF-1α could be demonstrated under those conditions.
- Stated: whether O₂-dependent interaction of HIF-1α and VHL is required for recruitment of FIH-1 remains unanswered; an alternative but not mutually exclusive hypothesis is that FIH-1 and VHL recruit distinct HDAC complexes.
- Evident: many interaction and repression conclusions rely on overexpression and in vitro binding assays; FIH-1’s weaker HDAC binding and the possibilities that it interacts with HDAC-4–7, another corepressor, or possesses intrinsic HDAC activity are speculative and not demonstrated.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interaction of VHL and FIH-1 with histone deacetylases.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Functional interaction of FIH-1 and VHL to repress HIF-1␣ transactivation domain function.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Effect of FIH-1 on HIF-1-mediated reporter gene transcription.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interaction of FIH-1, HIF-1␣, and VHL in vitro.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Identification of FIH-1 by yeast two-hybrid screen.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The physical interaction of bait and prey proteins within yeast cells functionally reconstitutes an active GAL4 transcription factor, resulting in expression of genes containing upstream GAL4-binding sites that mediate histidine auxotrophy and α-gal expression.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interaction of FIH-1 and HIF-1␣ in human cells.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Localization of HIF-1␣ residues interacting with FIH-1.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“binding of VHL to the intact HIF-1␣ regulatory domain (residues 531-826) does not require preincubation of HIF-1␣ with cellular lysate (as a source of putative prolyl hydroxylase activity; Fig. 4D)”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TBLASTN searches revealed similarity of FIH-1 to the rat PASS1 protein (GenBank accession no.AF168362.1),proteins encoded by human ESTs FLJ13798 (AK023860.1)and FLJ20656 (AK000663.1),as well as to open reading frames in Caenorhabditis briggsae (AC084551.1)and Drosophila melanogaster (AE003469.2,AE003537.2) genomic DNA, thus defining a family of related proteins that has been conserved through inve”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Identification of FIH-1 in a screen for HIF-1␣-interacting proteins
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Thus, FIH-1 loss-of-function may contribute to increased HIF-1-mediated transactivation of downstream target genes such as VEGF in gliomas and other human cancers (Semenza 2000; Zagzag et al. 2000).”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Discussion
What the sources say
- Not checked yetcites Semenza 2000
- Not checked yetcites Zagzag et al. 2000
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 4
- Probably not a substantial claim. 3
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nucleotide sequence analysis revealed that the prey vector contained a 2.98-kb human cDNA encoding a 349-amino-acid protein that was subsequently designated FIH-1 (GenBank accession no.AF395830).”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Identification of FIH-1 in a screen for HIF-1␣-interacting proteins
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis of genomic DNA sequences deposited in Gen-Bank revealed that the FIH1 gene is present in contig NT 008635, which is mapped to human chromosome 10q24, and consists of eight exons and seven introns that span 14 kb of DNA.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Identification of FIH-1 in a screen for HIF-1␣-interacting proteins
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither FIH-1 nor VHL alone inhibited GalL-mediated transactivation, whereas the combination of FIH-1 and VHL resulted in significant transcriptional repression.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Inhibition of HIF-1␣ transactivation domain function by VHL and FIH-1 in human cells
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“EST data indicate that FIH-1 is expressed in multiple cell types derived from adrenal, bladder, brain (adult and fetal), breast, colon, embryo, foreskin, germ cell, heart, kidney, lung, lymph, marrow, muscle, nerve, ovary, parathyroid, prostate, skin, testis, tonsil, and uterus.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Identification of FIH-1 in a screen for HIF-1␣-interacting proteins
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Negative regulation of HIF-1␣ protein stability and transcriptional activity under nonhypoxic conditions mediated by VHL and FIH-1.”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Immunoprecipitation assay
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Elongins B and C and cullin 2 are required for E3 ubiquitin-protein ligase activity, whereas HDACs repress transactivation.
In the paper
“Residues 576-785 comprise an inhibitory domain the deletion of which increases transactivation domain function especially under nonhypoxic conditions (Jiang et al. 1997).”
§ FIH-1: a novel protein that interacts with HIF-1␣ and VHL to mediate repression of HIF-1 transcriptional activity > Abstract
What the sources say
- Not checked yetcites Jiang et al. 1997
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
HIF-1 activity is induced by hypoxia in all cell types.
“Because HIF-1 activity is induced by hypoxia in all cell types, the interaction of HIF-1 with other proteins is likely to play a major role in determining its biological activity.”
The paper relies on this without support.
HIF-1α contains basic helix-loop-helix (bHLH) and PAS domains required for dimerization and DNA binding, a proline/serine/threonine-rich protein stabilization domain (PSTD), two transactivation domains (TAD-N and TAD-C), and an inhibitory domain (ID) that negatively regulates transactivation domain function under nonhypoxic conditions.
“HIF-1␣ contains basic helix-loop-helix (bHLH) and PAS domains that are required for dimerization and DNA binding, a proline/serine/threonine-rich protein stabilization domain (PSTD), two transactivation domains (TAD-N and TAD-C), and an inhibitory domain (ID) that negatively regulates transactivation domain function under nonhypoxic conditions.”
The paper relies on this without support.
Elongins B and C and cullin 2 are required for E3 ubiquitin-protein ligase activity, whereas HDACs repress transactivation.
“Elongins B and C and cullin 2 are required for E3 ubiquitin-protein ligase activity, whereas HDACs repress transactivation.”
The paper relies on this without support.
The physical interaction of bait and prey proteins within yeast cells functionally reconstitutes an active GAL4 transcription factor, resulting in expression of genes containing upstream GAL4-binding sites that mediate histidine auxotrophy and α-gal expression.
“The physical interaction of the bait and prey proteins within yeast cells functionally reconstitutes an active GAL4 transcription factor, resulting in the expression of genes that contain upstream GAL4-binding sites and mediate histidine auxotrophy (his + ) and ␣-gal expression.”
Claims other papers make about this one
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“although it remains capable of binding the CAD under these conditions (Mahon et al. 2001).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Mahon et al. 2001
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“HIF transcriptional activity is also regulated by a second oxygen-sensitive hydroxylation event mediated by factor inhibiting HIF-1 (FIH-1) (Mahon et al., 2001;Lando et al., 2002).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Mahon et al., 2001
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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 [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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 [52]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Although the two modes of regulation can be apparently uncoupled from each other through the construction of chimeras containing either the ODD or the CAD, the machinery regulating the two appears to be linked (Mahon et al. 2001).”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Mahon et al. 2001
The cited source says what the claim attributes to it.
In the citing paper
“In vitro binding studies suggest that FIH-1 and pVHL interact and may be part of a larger complex that represses HIF by multiple mechanisms under normoxic conditions (Mahon et al. 2001)”
From FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor (2002) · cites this paper as Mahon et al. 2001
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 [45]
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Metadata
- Authors
- Mahon, P. C., Hirota, K., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-10-15
- Volume
- 15
- Issue
- 20
- Pages
- 2675-2686
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC312814
- OpenAlex
- W2089692551
- Semantic Scholar
- 76cac1c7209112ecf9989f7cc81e563b7881292c
- Cited by
- 1,385
- References
- 47
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 40 · 2023: 52 · 2022: 63 · 2021: 71 · 2020: 58 · 2019: 64 · 2018: 47 · 2017: 50 · 2016: 61 · 2015: 60 · 2014: 54 · 2013: 56 · 2012: 59
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uehara Memorial Foundation
- National Institutes of Health (5r01dk039869-16)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- FIH-1, HIF-1α, VHL, HIF-1, transcriptional repression, histone deacetylase, corepressors, oxygen sensing, protein-protein interaction, ubiquitination, proteasomal degradation, oxygen homeostasis
- MeSH terms
- Amino Acid Sequence, Animals, Cells, Cultured, DNA-Binding Proteins, Fungal Proteins, Gene Expression Regulation, Glutathione Transferase, Histone Deacetylases, Humans, Mixed Function Oxygenases, Ligases, Luciferases, Molecular Sequence Data, Nuclear Proteins, Oxygen, Protein Conformation, Rabbits, Repressor Proteins, Reticulocytes, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Signal Transduction, Transcriptional Activation, Cell Hypoxia, Polymerase Chain Reaction, Sequence Homology, Amino Acid, DNA Primers, Two-Hybrid System Techniques, Tumor Suppressor Proteins, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques
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