HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation

Yu, Fang; White, Sarah B.; Zhao, Quan; Lee, Frank S.

doi:10.1073/pnas.181341498

Cited by 796Cancer, Hypoxia, and MetabolismUbiquitin and proteasome pathwaysErythropoietin and Anemia Treatment

HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation

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Yu, Fang, White, Sarah B., Zhao, Quan, Lee, Frank S.·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.181341498PMC PMC55503

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) 1 is a global transcriptional regulator of the hypoxic response. Under normoxic conditions, HIF-1α is recognized by the von Hippel-Lindau tumor-suppressor protein (VHL), a component of an E3 ubiquitin ligase complex. This interaction thereby promotes the rapid degradation of HIF-1α. Under hypoxic conditions, HIF-1α is stabilized. We have previously shown that VHL binds in a hypoxia-sensitive manner to a 27-aa segment of HIF-1α, and that this regulation depends on a posttranslational modification of HIF-1α. Through a combination of in vivo coimmunoprecipitation assays using VHL and a panel of point mutants of HIF-1α in this region, as well as MS and in vitro binding assays, we now provide evidence that this modification, which occurs under normoxic conditions, is hydroxylation of Pro-564 of HIF-1α. The data furthermore show that this proline hydroxylation is the primary regulator of VHL binding.

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Hif-1α is hydroxylated on two conserved proline residues by PHD1-3, allowing VHL to bind, ubiquitinate, and target Hif-1α for proteasomal degradation.
“Hif-1α is hydroxylated on two highly conserved proline residues by prolyl hydroxylase enzymes (PHD1-3), which in turn allows the von Hippel–Lindau protein, an E3 ubiquitin ligase, to bind, ubiquitinate, and target Hif-1α for proteasomal degradation [41–43].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [42]
Under normoxic conditions, the VHL-HIF1α interaction is mediated through a hydroxyproline residue on HIF1α.
“Under normoxic conditions, the VHL–HIF1α interaction is mediated through a hydroxyproline residue on HIF1α [49].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [49]

Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei
Dignam, J. D., Lebovitz, R. M., & Roeder, R. G. (1983) · Nucleic Acids Research · doi:10.1093/nar/11.5.1475 · Cited by 11,262 · see citing works
Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase
Smith, D. B., & Johnson, K. S. (1988) · Gene · doi:10.1016/0378-1119(88)90005-4 · Cited by 5,974 · see citing works
Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation
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
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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
Regulation of hypoxia-inducible factor 1α is mediated by an O 2 -dependent degradation domain via the ubiquitin-proteasome pathway
Huang, 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
Regulation of Mammalian O 2 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
Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein
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
HIF-1 and mechanisms of hypoxia sensing
Semenza, G. L. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00194-0 · Cited by 1,267 · see citing works
Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein
Cockman, 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 the Erythropoietin Gene: Evidence That the Oxygen Sensor Is a Heme Protein
Goldberg, M. A., Dunning, S. P., & Bunn, H. F. (1988) · Science · doi:10.1126/science.2849206 · Cited by 1,032 · see citing works
Mechanism of regulation of the hypoxia‐inducible factor‐1α by the von Hippel‐Lindau tumor suppressor protein
Tanimoto, K., Makino, Y., Pereira, T., & Poellinger, L. (2000) · The EMBO Journal · doi:10.1093/emboj/19.16.4298 · Cited by 928 · see citing works
Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex
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
Induction of HIF–1α in response to hypoxia is instantaneous
Jewell, U. R., Kvietikova, I., Scheid, A., Bauer, C., Wenger, R. H., & Gassmann, M. (2001) · The FASEB Journal · doi:10.1096/fj.00-0732fje · Cited by 443 · see citing works
Vitamin K-Dependent Biosynthesis of γ-Carboxyglutamic Acid
Furie, B., Bouchard, B. A., & Furie, B. C. (1999) · Blood · doi:10.1182/blood.v93.6.1798.406k22_1798_1808 · Cited by 422 · see citing works
Collagen Hydroxylases and the Protein Disulfide Isomerase Subunit of Prolyl 4‐Hydroxylases
Kivirikko, K. I., & Pihlajaniemi, T. A. (1998) · Advances in enzymology and related areas of molecular biology/Advances in enzymology and related subjects · doi:10.1002/9780470123188.ch9 · Cited by 313 · see citing works
Effect of Protein Kinase and Phosphatase Inhibitors on Expression of Hypoxia Inducible Factor 1
Wang, G. L., Jiang, B., & Semenza, G. L. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2674 · Cited by 230 · see citing works
The von Hippel–Lindau Tumor Suppressor Gene
Kondo, K., & Kaelin, W. G. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5139 · Cited by 215 · see citing works
The von Hippel-Lindau Tumor Suppressor Gene
Elias, R. M., Zhang, Q. H., & Brugarolas, J. (2020) · The Cancer Journal · doi:10.1097/ppo.0000000000000480 · Cited by 209 · see citing works
Hypoxic Induction of Prolyl 4-Hydroxylase α(I) in Cultured Cells
Takahashi, Y., Takahashi, S., Shiga, Y., Yoshimi, T., & Miura, T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14139 · Cited by 174 · see citing works
Bacterial protein toxins targeting Rho GTPases
Lerm, M., Schmidt, G., & Aktories, K. (2000) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2000.tb09159.x · Cited by 93 · see citing works
Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein.
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · PubMed · Cited by 87 · 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
Intrinsically unstructured proteins and their functions
Dyson, H. J., & Wright, P. E. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1589 · Cited by 3,871 · see citing works
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549 · 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
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · see citing works
“In particular, elevated levels al., 2001; Jaakkola et al., 2001; Yu et al., 2001).”
Background
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
FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor
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
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
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
HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells
Fukuda, R., Zhang, H., Kim, J.-W., Shimoda, L., Dang, C. V., & Semenza, G. L. (2007) · Cell · doi:10.1016/j.cell.2007.01.047 · Cited by 1,225 · see citing works
Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · see citing works
“…elevated levels of HIF1a provided evidence that fumarate and succinate accumulated in cells with mutations in either FH or SDH inhibit prolyl hydroxylases (PHDs), which hydroxylates and promotes the degradation of HIF1a (Epstein et al. 2001; Yu et al. 2001; Isaacs et al. 2005; Selak et al. 2005).”
Background
Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin
Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186 · see citing works
Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
Manalo, D. J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B. D., Ye, S. Q., Garcia, J. G. N., & Semenza, G. L. (2005) · Blood · doi:10.1182/blood-2004-07-2958 · Cited by 1,154 · see citing works
Cellular adaptation to hypoxia: O 2 ‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O 2 ‐regulated gene expression
Wenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135 · see citing works
Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor
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
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
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865 · 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
Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling
Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G., & Pavletich, N. P. (2002) · Science · doi:10.1126/science.1073440 · Cited by 765 · see citing works
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751 · see citing works
Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
Kondo, K., Klco, J., Nakamura, E., Lechpammer, M., & Kaelin, W. G. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00043-0 · Cited by 761 · see citing works
Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family
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
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Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia
Cheng, J., Kang, X., Zhang, S., & Yeh, E. T. H. (2007) · Cell · doi:10.1016/j.cell.2007.08.045 · Cited by 624 · see citing works
Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation
Mansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., & Simon, M. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.003 · Cited by 606 · see citing works
Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor
Ivan, M., Haberberger, T., Gervasi, D. C., Michelson, K. S., Günzler, V., Kondo, K., Yang, H., Sorokina, I., Conaway, R. C., Conaway, J. W., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192342099 · 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
TSC2 regulates VEGF through mTOR-dependent and -independent pathways
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Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610415200 · Cited by 521 · see citing works
Targeting the HIF2–VEGF axis in renal cell carcinoma
Choueiri, T. K., & Kaelin, W. G. (2020) · Nature Medicine · doi:10.1038/s41591-020-1093-z · Cited by 477 · see citing works
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Mandriota, S. J., Turner, K. J., Davies, D. R., Murray, P. G., Morgan, N. V., Sowter, H. M., Wykoff, C. C., Maher, E. R., Harris, A. L., Ratcliffe, P. J., et al. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00071-5 · Cited by 483 · 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
Regulation of cancer cell metabolism by hypoxia-inducible factor 1
Semenza, G. L. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.11.009 · Cited by 469 · see citing works
Acute postnatal ablation of Hif-2 α results in anemia
Gruber, M., Hu, C.-J., Johnson, R. S., Brown, E. J., Keith, B., & Simon, M. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608382104 · Cited by 457 · see citing works
Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases
Koivunen, P., Hirsilä, M., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312254200 · Cited by 447 · 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
The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis
Lum, J. J., Bui, T., Gruber, M., Gordan, J. D., DeBerardinis, R. J., Covello, K. L., Simon, M. C., & Thompson, C. B. (2007) · Genes & Development · doi:10.1101/gad.1529107 · Cited by 429 · 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
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
Mucosal Protection by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition
Robinson, A., Keely, S., Karhausen, J., Gerich, M. E., Furuta, G. T., & Colgan, S. P. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.09.033 · Cited by 368 · see citing works
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Hypoxic regulation of erythropoiesis and iron metabolism
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The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma
Kaelin, W. G. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1865 · Cited by 336 · see citing works
Multiple Factors Affecting Cellular Redox Status and Energy Metabolism Modulate Hypoxia-Inducible Factor Prolyl Hydroxylase Activity In Vivo and In Vitro
Pan, Y., Mansfield, K. D., Bertozzi, C. C., Rudenko, V., Chan, D. A., Giaccia, A. J., & Simon, M. C. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01223-06 · Cited by 332 · see citing works
A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis
Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R. J., Maxwell, P. H., McMullin, M. F., & Lee, F. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508423103 · Cited by 330 · see citing works
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Safran, M., & Kaelin, W. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318181 · Cited by 365 · see citing works
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Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0406-x · Cited by 221 · see citing works
Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the β-carbon of asparagine-803
McNEILL, L. A., HEWITSON, K. S., CLARIDGE, T. D., SEIBEL, J. F., HORSFALL, L. E., & SCHOFIELD, C. J. (2002) · Biochemical Journal · doi:10.1042/bj20021162 · Cited by 215 · see citing works
Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
Ozer, A., & Bruick, R. K. (2007) · Nature Chemical Biology · doi:10.1038/nchembio863 · Cited by 214 · see citing works
Structure of factor-inhibiting hypoxia-inducible factor 1: an asparaginyl hydroxylase involved in the hypoxic response pathway
Dann, C. E., Bruick, R. K., & Deisenhofer, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202614999 · Cited by 200 · see citing works
The Hypoxia-Inducible Factor 2 α N-Terminal and C-Terminal Transactivation Domains Cooperate To Promote Renal Tumorigenesis In Vivo
Yan, Q., Bartz, S., Mao, M., Li, L., & Kaelin, W. G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01514-06 · Cited by 193 · see citing works
Redox regulation of the hypoxia-inducible factor
Pouysségur, J., & Mechta-Grigoriou, F. (2006) · Biological Chemistry · doi:10.1515/bc.2006.167 · Cited by 186 · see citing works
The VHL tumor suppressor: master regulator of HIF
Haase, V. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209789649394 · Cited by 175 · see citing works
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177 · see citing works
Self-citation
Tumor Necrosis Factor-α Causes Accumulation of a Ubiquitinated Form of Hypoxia Inducible Factor-1α through a Nuclear Factor-κB-Dependent Pathway
Zhou, J., Schmid, T., & Brüne, B. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-09-0598 · Cited by 177 · see citing works
Ascorbate as a co-factor for Fe- and 2-oxoglutarate dependent dioxygenases: Physiological activity in tumor growth and progression
Kuiper, C., & Vissers, M. C. M. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00359 · Cited by 163 · see citing works
A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove
Percy, M. J., Furlow, P. W., Beer, P. A., Lappin, T. R. J., McMullin, M. F., & Lee, F. S. (2007) · Blood · doi:10.1182/blood-2007-04-084434 · Cited by 155 · see citing works
Self-citation
A binding motif for Siah ubiquitin ligase
House, C. M., Frew, I. J., Huang, H.-L., Wiche, G., Traficante, N., Nice, E., Catimel, B., & Bowtell, D. D. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0534783100 · Cited by 148 · see citing works
2-Oxoglutarate analogue inhibitors of hif prolyl hydroxylase
Mole, D. R., Schlemminger, I., McNeill, L. A., Hewitson, K. S., Pugh, C. W., Ratcliffe, P. J., & Schofield, C. J. (2003) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(03)00539-0 · Cited by 145 · see citing works
Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1α Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP
Sang, N., Fang, J., Srinivas, V., Leshchinsky, I., & Caro, J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.9.2984-2992.2002 · Cited by 143 · see citing works
The von Hippel-Lindau gene, kidney cancer, and oxygen sensing.
Kaelin, W. G. (2003) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000092803.69761.41 · Cited by 135 · see citing works
Mitochondrial regulation of oxygen sensing
Bell, E. L., Emerling, B. M., & Chandel, N. S. (2005) · Mitochondrion · doi:10.1016/j.mito.2005.06.005 · Cited by 130 · see citing works
The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases
Koivunen, P., Hirsilä, M., Kivirikko, K. I., & Myllyharju, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604628200 · Cited by 129 · see citing works
Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis
Percy, M. J., Beer, P. A., Campbell, G., Dekker, A. W., Green, A. R., Oscier, D., Rainey, M. G., van Wijk, R., Wood, M., Lappin, T. R. J., et al. (2008) · Blood · doi:10.1182/blood-2008-02-137703 · Cited by 127 · see citing works
Self-citation
The use of dioxygen by HIF prolyl hydroxylase (PHD1)
McNeill, L. A., Hewitson, K. S., Gleadle, J. M., Horsfall, L. E., Oldham, N. J., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., & Schofield, C. J. (2002) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(02)00219-6 · Cited by 116 · see citing works
Chromatin and oxygen sensing in the context of JmjC histone demethylases
Shmakova, A., Batie, M., Druker, J., & Rocha, S. (2014) · Biochemical Journal · doi:10.1042/bj20140754 · Cited by 99 · see citing works
Advances in targeted degradation of endogenous proteins
Röth, S., Fulcher, L. J., & Sapkota, G. P. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03112-6 · Cited by 92 · see citing works
An affinity-directed protein missile system for targeted proteolysis
Fulcher, L. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A., & Sapkota, G. P. (2016) · Open Biology · doi:10.1098/rsob.160255 · Cited by 91 · see citing works
Growth Factor-Mediated Induction of HDM2 Positively Regulates Hypoxia-Inducible Factor 1α Expression
Bárdos, J. I., Chau, N.-M., & Ashcroft, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.7.2905-2914.2004 · Cited by 87 · see citing works
Oxygen‐sensing mechanisms in cells
Wilson, J. W., Shakir, D., Batie, M., Frost, M., & Rocha, S. (2020) · The FEBS Journal · doi:10.1111/febs.15374 · Cited by 86 · see citing works
Targeting endogenous proteins for degradation through the affinity-directed protein missile system
Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C., & Sapkota, G. P. (2017) · Open Biology · doi:10.1098/rsob.170066 · Cited by 79 · see citing works
Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis
Laitala, A., Aro, E., Walkinshaw, G., Mäki, J. M., Rossi, M., Heikkilä, M., Savolainen, E.-R., Arend, M., Kivirikko, K. I., Koivunen, P., et al. (2012) · Blood · doi:10.1182/blood-2012-07-441824 · Cited by 58 · see citing works
Erythrocytosis-associated HIF-2α Mutations Demonstrate a Critical Role for Residues C-terminal to the Hydroxylacceptor Proline
Furlow, P. W., Percy, M. J., Sutherland, S., Bierl, C., McMullin, M. F., Master, S. R., Lappin, T. R. J., & Lee, F. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808737200 · Cited by 58 · see citing works
Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition
Li, C., Fu, C., Zhou, W., Li, H., Liu, Z., Wu, G., He, T., Shen, M., & Liu, H. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02366-x · Cited by 45 · see citing works
Perspectives on Hypoxia Signaling in Tumor Stroma
Zhang, Y., Coleman, M., & Brekken, R. A. (2021) · Cancers · doi:10.3390/cancers13123070 · Cited by 39 · see citing works
HIF gene expression in cancer therapy
Chan, D. A., Krieg, A. J., Turcotte, S., & Giaccia, A. J. (2007) · Methods in Enzymology · doi:10.1016/s0076-6879(07)35016-7 · Cited by 26 · see citing works
Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype
Isidor, B., Ebstein, F., Hurst, A., Vincent, M., Bader, I., Rudy, N. L., Cogne, B., Mayr, J., Brehm, A., Bupp, C., et al. (2022) · Genetics in Medicine · doi:10.1016/j.gim.2021.09.005 · Cited by 24 · see citing works
HIF1α is not a target of 14q deletion in clear cell renal cancer
Shenoy, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-74631-7 · Cited by 14 · see citing works

A reducing and denaturing step maximizes the immunoprecipitations of m-calpain and I-2PP2A/SET: An approach toward antibodies that do not work well in immunoprecipitation
Chen, W., Nishikimi, A., Kamata, T., et al. (2006) · Journal of Biochemical and Biophysical Methods · doi:10.1016/j.jbbm.2006.02.012 · Cited by 4 · see citing works
Co-Immunoprecipitation from Transfected Cells
Masters, S. C. (2004) · Humana Press eBooks · doi:10.1385/1-59259-762-9:337 · Cited by 66 · see citing works
Chapter 23 Immunoprecipitation Procedures
Williams, N. E. (1999) · Methods in cell biology · doi:10.1016/s0091-679x(08)61549-6 · Cited by 40 · see citing works
Protein Coimmunoprecipitation in ArabidopsisPreprint
Serino, G., & Deng, X. (2007) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot4683 · Cited by 12 · see citing works
Immunoprecipitation for Cell Culture
Zhu, H. (2012) · BIO-PROTOCOL · doi:10.21769/bioprotoc.72

Authors: Yu, F., White, S. B., Zhao, Q., & Lee, F. S.
Affiliations: University of Pennsylvania (US)
Harvard University (US)
Corresponding author: Lee, Frank S.
ORCID: Yu, Fang
Zhao, Quan
Lee, Frank S.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2001-08-14
Volume: 98
Issue: 17
Pages: 9630-9635
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.181341498
PMC: PMC55503
OpenAlex: W2011562442
Cited by: 796
References: 22
Citations by year: 2026: 21 · 2025: 29 · 2024: 23 · 2023: 38 · 2022: 20 · 2021: 27 · 2020: 27 · 2019: 16 · 2018: 18 · 2017: 22 · 2016: 24 · 2015: 30 · 2014: 32 · 2013: 36 · 2012: 28
FWCI: 17.55
Type: journal article
Language: en
Update notices: correction (2001-11-27)
correction (2001-12-04)
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: W. W. Smith Charitable Trust
National Institutes of Health (5r01dk055672-04)
National Institute of Diabetes and Digestive and Kidney Diseases (DK55672)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords: HIF-1α, von Hippel-Lindau protein, proline hydroxylation, HIF-1α degradation, hypoxia, protein-protein interaction, E3 ubiquitin ligase, post-translational modification, transcriptional regulation
MeSH terms: Amino Acid Sequence, Animals, Chlorocebus aethiops, Cobalt, DNA-Binding Proteins, HeLa Cells, Humans, Hydroxylation, Hydroxyproline, Ligases, Molecular Sequence Data, Nuclear Proteins, Peptide Fragments, Proline, Protein Binding, Protein Processing, Post-Translational, Proteins, Recombinant Fusion Proteins, Transcription Factors, Transfection, Cell Hypoxia, Point Mutation, COS Cells, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Macromolecular Substances, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit

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HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation

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