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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Claims the paper makes
0 of 7 cited sources checked · 0 supported · 0 flagged
- Findingown data
VHL and FIH-1 interact with histone deacetylases.
“Interaction of VHL and FIH-1 with histone deacetylases.”
Quote in the paperSubstantial claim - Findingown data
FIH-1 and VHL functionally interact to repress HIF-1α transactivation domain function.
“Functional interaction of FIH-1 and VHL to repress HIF-1␣ transactivation domain function.”
Quote in the paperSubstantial claim - Findingown data
FIH-1 affects HIF-1-mediated reporter gene transcription.
“Effect of FIH-1 on HIF-1-mediated reporter gene transcription.”
Quote in the paperSubstantial claim - Findingown data
FIH-1, HIF-1α, and VHL interact in vitro.
“Interaction of FIH-1, HIF-1␣, and VHL in vitro.”
Quote in the paperSubstantial claim - Findingown data
FIH-1 was identified by yeast two-hybrid screen.
“Identification of FIH-1 by yeast two-hybrid screen.”
Quote in the paperSubstantial claim- 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.
- Findingown data
FIH-1 and HIF-1α interact in human cells.
“Interaction of FIH-1 and HIF-1␣ in human cells.”
Quote in the paperSubstantial claim - Findingown data
HIF-1α residues interact with FIH-1.
“Localization of HIF-1␣ residues interacting with FIH-1.”
Quote in the paperSubstantial claim - Findingown data
Binding of VHL to the intact HIF-1α regulatory domain (residues 531-826) does not require preincubation of HIF-1α with cellular lysate.
“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)”
Quote in the paperSubstantial claim - Findingown data
FIH-1 is the founder of a family of proteins conserved through invertebrate and vertebrate evolution.
“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”
Quote in the paperNot a substantial claim - Interpretationreasoning
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.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Semenza 2000
Not checked in the free run.
- cites Zagzag et al. 2000
Not checked in the free run.
- Premisecitation
Transactivation domain function is negatively regulated by O2 independently of protein stability.
“Transactivation domain function is negatively regulated by O 2 independently of protein stability.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Jiang et al. 1997
Not checked in the free run.
- cites Pugh et al. 1997
Not checked in the free run.
- Interpretationreasoning
Ternary complex formation is likely to involve cooperativity.
“Because each protein interacts with the other two via independent binding sites, ternary complex formation is likely to involve cooperativity, an hypothesis that is supported by the transactivation studies (Fig. 6A).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Loss of VHL function in RCC may be sufficient for constitutive transcription of HIF-1 target genes.
“These results indicate that loss of VHL function in RCC may be sufficient for constitutive transcription of HIF-1 target genes.”
Quote in the paperSubstantial claim - Interpretationreasoning
Loss of either VHL or FIH-1 activity may be sufficient to derepress transactivation.
“This relationship implies that loss of either VHL or FIH-1 activity may be sufficient to derepress transactivation.”
Quote in the paperSubstantial claim - Interpretationown data
Negative regulation of HIF-1α by VHL may be controlled by factors in addition to the O2-dependent hydroxylation of Pro 564.
“suggest that negative regulation of HIF-1␣ by VHL may be controlled by factors in addition to the O 2 -dependent hydroxylation of Pro 564 (Ivan et al. 2001;Jaakkola et al. 2001)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Ivan et al. 2001
Not checked in the free run.
- cites Jaakkola et al. 2001
Not checked in the free run.
- Interpretationown data
The results establish a unifying mechanism for the modulation of HIF-1α protein stabilization and transcriptional activation in response to changes in cellular O2 concentration, mediated by VHL in association with FIH-1.
“Most importantly, the results reported here establish a unifying mechanism for the modulation of HIF-1␣ protein stabilization and transcriptional activation in response to changes in cellular O 2 concentration that is mediated by VHL in association with FIH-1.”
Quote in the paperSubstantial claim - Study design and conductown data
The two-hybrid interaction was confirmed by retransformation of yeast strain Y190 with the bait vector and purified prey plasmid, demonstrating that the resulting transformants were again his+ and expressed α-gal.
“the two-hybrid interaction was confirmed by retransformation of yeast strain Y190 with the bait vector and purified prey plasmid to demonstrate that the resulting transformants were again his + and expressed ␣-gal.”
Quote in the paperSubstantial claim - Interpretationown data
HIF-1α, FIH-1, and VHL have a complex functional relationship.
“The complex functional relationship between HIF-1␣, FIH-1, and VHL documented in this study”
Quote in the paperSubstantial claim
- May combine two claims. 4
- Classified as probably not a substantial claim. 3
May combine two claims.
Findingown dataFIH-1 was identified as a 349-amino-acid protein encoded by a 2.98-kb human cDNA.
“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).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe FIH1 gene is located at human chromosome 10q24 and consists of eight exons and seven introns spanning 14 kb.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNeither FIH-1 nor VHL alone inhibits GalL-mediated transactivation, whereas the combination of FIH-1 and VHL results in significant transcriptional repression.
“Neither FIH-1 nor VHL alone inhibited GalL-mediated transactivation, whereas the combination of FIH-1 and VHL resulted in significant transcriptional repression.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFIH-1 is expressed in multiple cell types.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataVHL and FIH-1 mediate negative regulation of HIF-1α protein stability and transcriptional activity under nonhypoxic conditions.
“Negative regulation of HIF-1␣ protein stability and transcriptional activity under nonhypoxic conditions mediated by VHL and FIH-1.”
Quote in the paperSubstantial claim- Rests on an assumption: Elongins B and C and cullin 2 are required for E3 ubiquitin-protein ligase activity, whereas HDACs repress transactivation.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationResidues 576-785 of HIF-1α comprise an inhibitory domain whose deletion increases transactivation domain function especially under nonhypoxic conditions.
“Residues 576-785 comprise an inhibitory domain the deletion of which increases transactivation domain function especially under nonhypoxic conditions (Jiang et al. 1997).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Jiang et al. 1997
Not checked in the free run.
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
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FIH-1 remains capable of binding the CAD under conditions without excess Fe(II) and 2-oxoglutarate.
“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
The “Interaction of FIH-1 with HIF-1α in vitro” section reports binding to HIF-1α fragments that include the C-terminal activation domain (CAD), but says the isolated domain (residues 786–826) did not bind FIH-1. The paper does not establish binding specifically under conditions without excess Fe(II) and 2-oxoglutarate. Page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHIF transcriptional activity is also regulated by a second oxygen-sensitive hydroxylation event mediated by FIH-1.
“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
The Abstract and Discussion describe FIH-1 as a negative regulator of HIF-1α transcriptional activity associated with oxygen-dependent regulation. They do not identify FIH-1 as mediating a second hydroxylation event; the hydroxylation discussed in the paper is oxygen-dependent hydroxylation of Pro 564 in connection with VHL binding. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredFIH-1-mediated repression attenuates HIF transcriptional activity during early reoxygenation, acting as a buffer that limits excessive metabolic activation and oxidative stress during the transition from hypoxia to normoxia.
“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]
The section “FIH-1 inhibits transcriptional activation mediated by HIF-1α in human cells” reports that FIH-1 reduced HIF-dependent reporter expression. The Discussion also describes FIH-1 and VHL as repressing HIF-1α activity under nonhypoxic conditions. The paper does not establish that this occurs during early reoxygenation or that it buffers metabolic activation or oxidative stress during the transition to normoxia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFIH-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.
“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]
The Discussion and in-vitro interaction section (page numbers unavailable) show that FIH-1 interacts with the C-terminal region of HIF-1α and represses its transactivation function; the paper also identifies coactivators that bind the C-terminal transactivation domain. Our copy does not establish that FIH-1 hydroxylates an asparagine, blocks coactivator engagement by that mechanism, or functions at lower oxygen tensions than PHDs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe machinery regulating ODD and CAD appears to be linked.
“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
FIH-1 and pVHL interact and may be part of a larger complex that represses HIF by multiple mechanisms under normoxic conditions.
“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
Hif-1α is hydroxylated on a conserved asparagine residue by FIH-1, which blocks recruitment of transcriptional coactivators such as p300/CBP, limiting transcriptional activation under non-hypoxic conditions.
“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]
Cites
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212 · see citing works
Self-citationA novel genetic system to detect protein–protein interactions
Fields, S., & Song, O.-K. (1989) · Nature · doi:10.1038/340245a0 · Cited by 6,152 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502 · see citing works
Hoffman, C. S., & Winston, F. (1987) · Gene · doi:10.1016/0378-1119(87)90131-4 · Cited by 2,492 · see citing works
Cellular and developmental control of O <sub>2</sub> homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476 · see citing works
Self-citationHuang, L. E., Gu, J., Schau, M., & Bunn, H. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7987 · Cited by 2,113 · see citing works
Purification and Characterization of Hypoxia-inducible Factor 1
Wang, G. L., & Semenza, G. L. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.3.1230 · Cited by 2,069 · see citing works
Self-citationRegulation of Mammalian O <sub>2</sub> Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914 · see citing works
Self-citationSemenza, G. L., Jiang, B.-H., Leung, S. W., Passantino, R., Concordet, J.-P., Maire, P., & Giallongo, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32529 · Cited by 1,752 · see citing works
Self-citationSalceda, S., & Caro, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.36.22642 · Cited by 1,674 · see citing works
Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T.-Y., Huang, L. E., Pavletich, N., Chau, V., & Kaelin, W. G. (2000) · Nature Cell Biology · doi:10.1038/35017054 · Cited by 1,577 · see citing works
(2000) · PubMed · Cited by 1,445 · see citing works
Self-citationLaughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · see citing works
Self-citationThe Multiple Roles of PTEN in Tumor Suppression
Di Cristofano, A., & Pandolfi, P. P. (2000) · Cell · doi:10.1016/s0092-8674(00)80674-1 · Cited by 1,182 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.
Ravi, R. K., Mookerjee, B., Bhujwalla, Z. M., Sutter, T. R., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · PubMed Central · Cited by 1,099 · see citing works
Self-citationCockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G.-W., Clifford, S. C., Maher, E. R., Pugh, C. W., Ratcliffe, P. J., & Maxwell, P. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002740200 · Cited by 1,053 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · Genes & Development · doi:10.1101/gad.14.1.34 · Cited by 967 · see citing works
Self-citationTanimoto, K., Makino, Y., Pereira, T., & Poellinger, L. (2000) · The EMBO Journal · doi:10.1093/emboj/19.16.4298 · Cited by 928 · see citing works
HIF-1 and human disease: one highly involved factor
Semenza, G. L. (2000) · Genes & Development · doi:10.1101/gad.14.16.1983 · Cited by 909 · see citing works
Self-citationLoss of <i>PTEN</i> facilitates HIF-1-mediated gene expression
Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., Gottschalk, A. R., Ryan, H. E., Johnson, R. S., Jefferson, A. B., et al. (2000) · Genes & Development · doi:10.1101/gad.14.4.391 · Cited by 840 · see citing works
Stabilization of wild-type p53 by hypoxia-inducible factor 1α
An, W. G., Kanekal, M., Simon, M. C., Maltepe, E., Blagosklonny, M. V., & Neckers, L. Μ. (1998) · Nature · doi:10.1038/32925 · Cited by 820 · see citing works
An essential role for p300/CBP in the cellular response to hypoxia
Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., & Livingston, D. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.23.12969 · Cited by 790 · see citing works
Richard, D. E., Berra, E., Gothié, E., Roux, D., & Pouysségur, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32631 · Cited by 790 · see citing works
Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia
Bruick, R. K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.16.9082 · Cited by 767 · see citing works
Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes
Kim, M. S., Kwon, H. J., Lee, Y. M., Baek, J. H., Jang, J.-E., Lee, S.-W., Moon, E.-J., Kim, H.-S., Lee, S., Chung, H. Y., et al. (2001) · Nature Medicine · doi:10.1038/86507 · Cited by 732 · see citing works
Kamura, T., Sato, S., Iwaï, K., Czyzyk-Krzeska, M., Conaway, R. C., & Conaway, J. W. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.190332597 · Cited by 652 · see citing works
Transactivation and Inhibitory Domains of Hypoxia-inducible Factor 1α
Jiang, B.-H., Zheng, J. Z., Leung, S. W., Roe, R., & Semenza, G. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19253 · Cited by 629 · see citing works
Self-citationExpression of hypoxia-inducible factor 1? in brain tumors
Zagzag, D., Zhong, H., Scalzitti, J. M., Laughner, E., Simons, J. W., & Semenza, G. L. (2000) · Cancer · doi:10.1002/1097-0142(20000601)88:11 · Cited by 603 · see citing works
Self-citationEma, M., Hirota, K., Mimura, J., Abe, H., Yodoi, J., Sogawa, K., Poellinger, L., & Fujii‐Kuriyama, Y. (1999) · The EMBO Journal · doi:10.1093/emboj/18.7.1905 · Cited by 588 · see citing works
Self-citationActivation of Hypoxia-inducible Factor-1; Definition of Regulatory Domains within the α Subunit
Pugh, C. W., O'Rourke, J. F., Nagao, M., Gleadle, J., & Ratcliffe, P. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.17.11205 · Cited by 526 · see citing works
Sodhi, A., Montaner, S., Patel, V., Zohar, M., Bais, C., Mesri, E. A., & Gutkind, J. S. (2000) · PubMed · Cited by 452 · see citing works
Yang, W., Yao, Y., Sun, J.-M., Davie, J., & Seto, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.28001 · Cited by 433 · see citing works
Kao, H., Downes, M., Ordentlich, P., & Evans, R. M. (2000) · Genes & Development · doi:10.1101/gad.14.1.55 · Cited by 424 · see citing works
Carrero, P., Okamoto, K., Coumailleau, P., O’Brien, S. L., Tanaka, H., & Poellinger, L. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.1.402-415.2000 · Cited by 382 · see citing works
Hoffman, M. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1019 · Cited by 382 · see citing works
Clifford, S. C. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1029 · Cited by 373 · see citing works
Sutter, T. R., Laughner, E., & Semenza, G. L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.080072497 · Cited by 299 · see citing works
Self-citationFormation of the VHL–Elongin BC Tumor Suppressor Complex Is Mediated by the Chaperonin TRiC
Feldman, D. E., Thulasiraman, V., Ferreyra, R. G., & Frydman, J. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80233-6 · Cited by 238 · see citing works
Cytogenetics and Molecular Genetics of Malignant Gliomas and Medulloblastoma
Bigner, S. H., & Vogelstein, B. (1990) · Brain Pathology · doi:10.1111/j.1750-3639.1990.tb00633.x · Cited by 158 · see citing works
Cheng, L., Qasba, P., Vanguri, P., & Thiede, M. A. (2000) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(200007)184:1 · Cited by 136 · see citing works
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · PubMed · Cited by 87 · see citing works
Transcription Factors and Human Disease
Semenza, G. L. (1998) · Cited by 39 · see citing works
Self-citationTranscription Factors and Huinan Disease
Semenza, G. L. (1998) · doi:10.1093/oso/9780195112399.001.0001 · Cited by 16 · see citing works
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Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · see citing works
Self-citationHypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · see citing works
Self-citationXu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · see citing works
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380 · see citing works
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,638 · see citing works
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · see citing works
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550 · see citing works
Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation
Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B., & Simon, M. C. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.24.9361-9374.2003 · Cited by 1,386 · see citing works
The impact of O2 availability on human cancer
Bertout, J. A., Patel, S. A., & Simon, M. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2540 · Cited by 1,365 · see citing works
Hypoxia-Induced Angiogenesis: Good and Evil
Krock, B. L., Skuli, N., & Simon, M. C. (2011) · Genes & Cancer · doi:10.1177/1947601911423654 · Cited by 1,179 · see citing works
Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology
Semenza, G. L. (2013) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012513-104720 · Cited by 1,159 · see citing works
Self-citationWenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135 · see citing works
Appelhoff, R. J., Tian, Y.-M., Raval, R. R., Turley, H., Harris, A. L., Pugh, C. W., Ratcliffe, P. J., & Gleadle, J. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406026200 · Cited by 1,108 · see citing works
HIF-1 and tumor progression: pathophysiology and therapeutics
Semenza, G. L. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02317-1 · Cited by 1,060 · see citing works
Self-citationThe hypoxic tumour microenvironment
Petrova, V., Annicchiarico‐Petruzzelli, M., Melino, G., & Amelio, I. (2018) · Oncogenesis · doi:10.1038/s41389-017-0011-9 · Cited by 1,035 · see citing works
Integration of Oxygen Signaling at the Consensus HRE
Wenger, R. H., Stiehl, D. P., & Camenisch, G. (2005) · Science's STKE · doi:10.1126/stke.3062005re12 · Cited by 1,032 · see citing works
Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology
Kierans, S. J., & Taylor, C. T. (2021) · The Journal of Physiology · doi:10.1113/jp280572 · Cited by 1,015 · see citing works
The role of oxygen availability in embryonic development and stem cell function
Simon, M. C., & Keith, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2354 · Cited by 966 · see citing works
Weidemann, A., & Johnson, R. S. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.12 · Cited by 941 · see citing works
Role of VHL Gene Mutation in Human Cancer
Kim, W. Y., & Kaelin, W. G. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.05.061 · Cited by 940 · see citing works
Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes
Hausinger, R. P. (2004) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230490440541 · Cited by 937 · see citing works
Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (2009) · Physiology · doi:10.1152/physiol.00045.2008 · Cited by 926 · see citing works
Self-citationHydroxylation of HIF-1: Oxygen Sensing at the Molecular Level
Semenza, G. L. (2004) · Physiology · doi:10.1152/physiol.00001.2004 · Cited by 901 · see citing works
Self-citationHypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity
Walmsley, S. R., Print, C., Farahi, N., Peyssonnaux, C., Johnson, R. S., Cramer, T., Sobolewski, A., Condliffe, A. M., Cowburn, A. S., Johnson, N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20040624 · Cited by 891 · see citing works
Signal transduction to hypoxia-inducible factor 1
Semenza, G. L. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01168-1 · Cited by 860 · see citing works
Self-citationROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection
Cadenas, S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.024 · Cited by 821 · see citing works
Fukuda, R., Hirota, K., Fan, F., Jung, Y. D., Ellis, L. M., & Semenza, G. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203781200 · Cited by 815 · see citing works
Self-citationThe role of hypoxia-inducible factors in tumorigenesis
Rankin, E. B., & Giaccia, A. J. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.21 · Cited by 806 · see citing works
Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor
Hirsilä, M., Koivunen, P., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304982200 · Cited by 794 · see citing works
Transcriptional regulation by hypoxia inducible factors
Dengler, V. L., Galbraith, M. D., & Espinosa, J. M. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.838205 · Cited by 774 · see citing works
Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α
Lim, J.-H., Lee, Y.-M., Chun, Y.-S., Chen, J., Kim, J.-E., & Park, J.-W. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.023 · Cited by 758 · see citing works
Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., Noguera, R., Navarro, S., Nilsson, H., Pietras, A., Vallon-Christersson, J., Borg, Å., Gradin, K., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.026 · Cited by 735 · see citing works
Hypoxia: A key regulator of angiogenesis in cancer
Liao, D., & Johnson, R. S. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9066-y · Cited by 720 · see citing works
Hewitson, K. S., McNeill, L. A., Riordan, M. V., Tian, Y.-M., Bullock, A. N., Welford, R. W., Elkins, J. M., Oldham, N. J., Bhattacharya, S., Gleadle, J. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200273200 · Cited by 719 · see citing works
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“oxygen-sensitive hydroxylation event mediated by factor inhibiting HIF-1 (FIH-1) (Mahon et al., 2001; Lando et al., 2002).”
BackgroundInfluentialAnti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?
Ramjiawan, R. R., Griffioen, A. W., & Duda, D. G. (2017) · Angiogenesis · doi:10.1007/s10456-017-9552-y · Cited by 674 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Self-citationHIF-1 as a target for drug development
Giaccia, A., Siim, B. G., & Johnson, R. S. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1199 · Cited by 631 · see citing works
Regulation of erythropoietin production
JELKMANN, W. E. B. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.195057 · Cited by 608 · see citing works
Rohwer, N., & Cramer, T. (2011) · Drug Resistance Updates · doi:10.1016/j.drup.2011.03.001 · Cited by 608 · see citing works
Zimna, A., & Kurpisz, M. (2015) · BioMed Research International · doi:10.1155/2015/549412 · Cited by 604 · see citing works
Umezu, T., Tadokoro, H., Azuma, K., Yoshizawa, S., Ohyashiki, K., & Ohyashiki, J. H. (2014) · Blood · doi:10.1182/blood-2014-05-576116 · Cited by 600 · see citing works
Hypoxia-inducible factors: cancer progression and clinical translation
Wicks, E. E., & Semenza, G. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159839 · Cited by 600 · see citing works
Self-citationPassing the baton: the HIF switch
Koh, M. Y., & Powis, G. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.06.004 · Cited by 589 · see citing works
JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress
Gerald, D., Berra, E., Frapart, Y. M., Chan, D. A., Giaccia, A. J., Mansuy, D., Pouysségur, J., Yaniv, M., & Mechta-Grigoriou, F. (2004) · Cell · doi:10.1016/j.cell.2004.08.025 · Cited by 588 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K
Courtnay, R., Ngo, D. C., Malik, N., Ververis, K., Tortorella, S. M., & Karagiannis, T. C. (2015) · Molecular Biology Reports · doi:10.1007/s11033-015-3858-x · Cited by 570 · see citing works
HIF1 and oxygen sensing in the brain
Sharp, F. R., & Bernaudin, M. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1408 · Cited by 569 · see citing works
Bell, E. L., Klimova, T. A., Eisenbart, J., Moraes, C. T., Murphy, M. P., Budinger, G. R. S., & Chandel, N. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200609074 · Cited by 568 · see citing works
The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer
Lin, A., Li, C., Xing, Z., Hu, Q., Liang, K., Han, L., Wang, C., Hawke, D. H., Wang, S., Zhang, Y., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3295 · Cited by 561 · see citing works
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1
Semenza, G. L. (2007) · Biochemical Journal · doi:10.1042/bj20070389 · Cited by 541 · see citing works
Self-citationSonveaux, P., Copetti, T., De Saedeleer, C. J., Végran, F., Verrax, J., Kennedy, K. M., Moon, E. J., Dhup, S., Danhier, P., Frérart, F., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033418 · Cited by 536 · see citing works
Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling
Rey, S., & Semenza, G. L. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq045 · Cited by 536 · see citing works
Self-citationThe use of cobalt chloride as a chemical hypoxia model
Muñoz‐Sánchez, J., & Chánez‐Cárdenas, M. E. (2018) · Journal of Applied Toxicology · doi:10.1002/jat.3749 · Cited by 535 · see citing works
The effect of HIF on metabolism and immunity
Taylor, C. T., & Scholz, C. C. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00587-8 · Cited by 517 · see citing works
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., et al. (2002) · Nature Genetics · doi:10.1038/ng1019 · Cited by 510 · see citing works
Self-citationMetabolic zonation of the liver: The oxygen gradient revisited
Kietzmann, T. (2017) · Redox Biology · doi:10.1016/j.redox.2017.01.012 · Cited by 499 · see citing works
Zheng, L., Kelly, C. J., & Colgan, S. P. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00191.2015 · Cited by 489 · see citing works
Semenza, G. L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.08.006 · Cited by 484 · see citing works
Self-citationLiu, Y. V., Baek, J. H., Zhang, H., Diez, R., Cole, R. N., & Semenza, G. L. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.01.001 · Cited by 477 · see citing works
Self-citationMolecular basis of skeletal muscle plasticity-from gene to form and function
Flück, M., & Hoppeler, H. H. (2003) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/s10254-002-0004-7 · Cited by 476 · see citing works
Regulation of Hypoxia-Inducible Factor 2α Signaling by the Stress-Responsive Deacetylase Sirtuin 1
Dioum, E. M., Chen, R., Alexander, M. S., Zhang, Q., Hogg, R. T., Gerard, R. D., & Garcia, J. A. (2009) · Science · doi:10.1126/science.1169956 · Cited by 470 · see citing works
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468 · see citing works
Hypoxic gene expression and metastasis
Le, Q., Denko, N. C., & Giaccia, A. J. (2004) · Cancer and Metastasis Reviews · doi:10.1023/b:canc.0000031768.89246.d7 · Cited by 466 · see citing works
Regulation of angiogenesis by hypoxia-inducible factor 1
Hirota, K., & Semenza, G. L. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.12.003 · Cited by 466 · see citing works
Self-citationHypoxia-responsive transcription factors
Cummins, E. P., & Taylor, C. T. (2005) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-005-1413-7 · Cited by 462 · see citing works
Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α
Freedman, S. J., Sun, Z., Poy, F., Kung, A. L., Livingston, D. M., Wagner, G., & Eck, M. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082117899 · Cited by 457 · see citing works
Hypoxia-inducible factors: central regulators of the tumor phenotype
Gordan, J. D., & Simon, M. C. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.12.006 · Cited by 450 · see citing works
Bruick, R. K. (2003) · Genes & Development · doi:10.1101/gad.1145503 · Cited by 435 · see citing works
Mitochondrial complex III regulates hypoxic activation of HIF
Klimova, T., & Chandel, N. S. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402307 · Cited by 433 · see citing works
Intracellular localisation of human HIF-1α hydroxylases:implications for oxygen sensing
Metzen, E., Berchner-Pfannschmidt, U., Stengel, P., Marxsen, J. H., Stolze, I., Klinger, M., Huang, W. Q., Wotzlaw, C., Hellwig-Bürgel, T., Jelkmann, W., et al. (2003) · Journal of Cell Science · doi:10.1242/jcs.00318 · Cited by 432 · see citing works
Role and regulation of prolyl hydroxylase domain proteins
Fong, G.-H., & Takeda, K. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.10 · Cited by 423 · see citing works
Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases
Metzen, E., Zhou, J., Jelkmann, W., Fandrey, J., & Brüne, B. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-12-0791 · Cited by 414 · see citing works
Nagao, A., Kobayashi, M., Koyasu, S., Chow, C. C. T., & Harada, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020238 · Cited by 411 · see citing works
Regulation of Osteogenesis-Angiogenesis Coupling by HIFs and VEGF
Schipani, E., Maes, C., Carmeliet, G., & Semenza, G. L. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.090602 · Cited by 407 · see citing works
Self-citationKoskenkorva-Frank, T. S., Weiss, G., Koppenol, W. H., & Burckhardt, S. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.09.001 · Cited by 406 · see citing works
Reversible Inactivation of HIF-1 Prolyl Hydroxylases Allows Cell Metabolism to Control Basal HIF-1
Lu, H., Dalgard, C. L., Mohyeldin, A., McFate, T., Tait, A. S., & Verma, A. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508718200 · Cited by 400 · see citing works
Warnecke, C., Zaborowska, Z., Kurreck, J., Erdmann, V. A., Frei, U. A., Wiesener, M. S., & Eckardt, K. (2004) · The FASEB Journal · doi:10.1096/fj.04-1640fje · Cited by 395 · see citing works
Elkins, J. M., Hewitson, K. S., McNeill, L. A., Seibel, J. F., Schlemminger, I., Pugh, C. W., Ratcliffe, P. J., & Schofield, C. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c200644200 · Cited by 391 · see citing works
The VHL/HIF axis in clear cell renal carcinoma
Shen, C., & Kaelin, W. G. (2012) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2012.06.001 · Cited by 387 · see citing works
Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer
Bae, T., Hallis, S. P., & Kwak, M. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01180-8 · Cited by 389 · see citing works
MARXSEN, J. H., STENGEL, P., DOEGE, K., HEIKKINEN, P., JOKILEHTO, T., WAGNER, T., JELKMANN, W., JAAKKOLA, P., & METZEN, E. (2004) · Biochemical Journal · doi:10.1042/bj20040620 · Cited by 386 · see citing works
The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease
Giaccia, A. J., Simon, M. C., & Johnson, R. (2004) · Genes & Development · doi:10.1101/gad.1243304 · Cited by 380 · see citing works
Hypoxia-Inducible Factors as Essential Regulators of Inflammation
Imtiyaz, H. Z., & Simon, M. C. (2010) · Current Topics in Microbiology and Immunology · doi:10.1007/82_2010_74 · Cited by 379 · see citing works
MAPK Signaling Up-regulates the Activity of Hypoxia-inducible Factors by Its Effects on p300
Sang, N., Stiehl, D. P., Bohensky, J., Leshchinsky, I., Srinivas, V., & Caro, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209702200 · Cited by 370 · see citing works
Erythropoietin after a century of research: younger than ever
JELKMANN, W. E. B. (2007) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2007.00818.x · Cited by 365 · see citing works
HIF hydroxylation and the mammalian oxygen-sensing pathway
Safran, M., & Kaelin, W. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18181 · Cited by 363 · see citing works
Nutrient Sensing, Metabolism, and Cell Growth Control
Yuan, H.-X., Xiong, Y., & Guan, K. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.019 · Cited by 357 · see citing works
Hu, C.-J., Sataur, A., Wang, L., Chen, H., & Simon, M. C. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-05-0419 · Cited by 355 · see citing works
Tumor hypoxia: A target for selective cancer therapy
Kizaka‐Kondoh, S., Inoue, M., Harada, H., & Hiraoka, M. (2003) · Cancer Science · doi:10.1111/j.1349-7006.2003.tb01395.x · Cited by 353 · see citing works
Hypoxic regulation of erythropoiesis and iron metabolism
Haase, V. H. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00174.2010 · Cited by 347 · see citing works
Regulation of Metabolism by Hypoxia-Inducible Factor 1
Semenza, G. L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010678 · Cited by 342 · see citing works
Self-citationBeyer, S., Kristensen, M. M., Jensen, K. S., Johansen, J. V., & Staller, P. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804578200 · Cited by 341 · see citing works
Martin, F., Linden, T., Katschinski, D. M., Oehme, F., Flamme, I., Mukhopadhyay, C. K., Eckhardt, K., Tröger, J., Barth, S., Camenisch, G., et al. (2005) · Blood · doi:10.1182/blood-2004-10-3980 · Cited by 340 · see citing works
Kaelin, W. G. (2006) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.2.010506.092049 · Cited by 335 · see citing works
Generating specificity and diversity in the transcriptional response to hypoxia
Lendahl, U., Lee, K. L., Yang, H. H., & Poellinger, L. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2665 · Cited by 330 · see citing works
Oxygen sensors and angiogenesis
Maxwell, P. H., & Ratcliffe, P. J. (2002) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.2001.0287 · Cited by 328 · see citing works
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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