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The VHL Tumor Suppressor: Master Regulator of HIF
Open accessAbstract
Hypoxia-Inducible Factors (HIFs) are heterodimeric oxygen-sensitive basic helix-loop-helix transcription factors that play central roles in cellular adaptation to low oxygen environments. The von-Hippel Lindau tumor suppressor (pVHL) is the substrate recognition component of an E3 ubiquitin ligase and functions as a master regulator of HIF activity by targeting the hydroxylated HIF-alpha subunit for ubiquitylation and rapid proteasomal degradation under normoxic conditions. Mutations in pVHL can be found in familial and sporadic hemangioblastomas, clear cell carcinomas of the kidney, pheochromocytomas and inherited forms of erythrocytosis, illustrating the importance of disrupted molecular oxygen sensing in the pathogenesis of these diseases. Tissue-specific gene targeting of pVHL in mice has demonstrated that efficient execution of HIF proteolysis is critically important for normal tissue physiology, and has provided novel insights into the functional consequences of HIF activation on the cellular and tissue level. Here we focus on the contribution of individual HIF transcription factors to the development of VHL phenotypes and discuss how the pVHL/HIF axis could be exploited pharmacologically.
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“Independently of hypoxia, HIFs can also become activated through the activation of oncogenes, or loss of tumor suppressor genes.”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [13]
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“Similarly, activation of RAS, PI-3K, or downstream ERK1/2 kinases, common in many cancer types, and loss of pVHL, frequently observed in clear cell renal cell carcinoma (ccRCC), result in hypoxia-independent activation of the HIFs [12–14].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [13]
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The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
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BackgroundMutations of the VHL tumour suppressor gene in renal carcinoma
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“HIF-1α protein is stabilized under hypoxia via reduced oxygen-dependent prolyl hydroxylation and decreased binding to the von Hippel–Lindau protein (VHL), a master regulator of HIF [21].”
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Ku, E., Vecchio, L. D., Eckardt, K., Haase, V. H., Johansen, K. L., Nangaku, M., Tangri, N., Waikar, S. S., Więcek, A., Cheung, M., et al. (2023) · Kidney International · doi:10.1016/j.kint.2023.05.009 · Cited by 162
Self-citationHypoxia and the phenomenon of immune exclusion
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“…VHL serves as a ubiquitin ligase receptor for modular cullin-2 ubiquitin ligases and mediates the constitutive ubiquitination and proteasomal degradation of HIF1 α under normoxic conditions (Haase, 2009), suggesting that overexpression as such will not alter cellular states at normal oxygen levels.”
STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection
Gomes, M. T. R., Guimarães, E. S., Marinho, F. V., Macedo, I., Aguiar, E. R. G. R., Barber, G. N., Moraes‐Vieira, P. M., Alves-Filho, J. C., & Oliveira, S. C. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009597 · Cited by 116
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“Activation of hypoxia-inducible genes leads to a metabolic shift to anerobic glycolysis, increased secretion of pro-angiogenic factors, remodeling of the extracellular matrix, resistance to apoptosis and increased mobility [27].”
BackgroundJeong, J., Gurunathan, S., Kang, M.-H., Han, J. W., Das, J., Choi, Y., Kwon, D., Cho, S., Park, C., Seo, H. G., et al. (2016) · Scientific Reports · doi:10.1038/srep21688 · Cited by 107
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“HIF1 a is hydroxylated by specific prolyl-hydroxylases and targeted for rapid proteasomal degradation by the von Hippel–Lindau (VHL) tumour suppressor 36 .”
Wang, Y., Ren, F., Wang, Y., Feng, Y., Wang, D., Jia, B., Qiu, Y., Wang, S., Yu, J. Q., Sung, J. J. �., et al. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt393 · Cited by 91
“[25, 26], FBXL2 [27, 28] and Cul9 [29], were identified as tumor suppressors that”
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“Somatic mutations in HIF2A (EPAS1), affecting PHD hydroxylation and subsequent VHL degradation, were recently recognized to cause a syndrome consisting of PGL and/or somatostatinoma (SOM) associated with polycythemia in females (Zhuang et al. 2012, Pacak et al.”
InfluentialThe Synergistic Cooperation between TGF-β and Hypoxia in Cancer and Fibrosis
Mallikarjuna, P., Zhou, Y., & Landström, M. (2022) · Biomolecules · doi:10.3390/biom12050635 · Cited by 84
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“Following hydroxylation, HIF-1a binds to the von Hippel–Lindau protein (pVHL) which is part of an E3-ubiquitin ligase complex that marks HIF-1a for proteasomal degradation through ubiquitination.(3) Oxygen is required for the function of PHDs.”
MethodInfluentialLow tumor glutathione level as a sensitivity marker for glutamate‑cysteine ligase inhibitors
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“PPP branches from glycolysis (18) that is known to be regulated by various cancer associated genes including hypoxia-inducible factor 1-α (19-21) whose expression is often upregulated by VHL deficiency (22).”
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“In well-oxygenated cells, the hydroxylation of proline residues by prolyl hydroxylase domain protein 2 promotes the interaction of HIF-1a and HIF-2a with the von-Hippel – Lindau tumor suppressor protein, which recruits an E3 ubiquitin-protein ligase and thus targets HIF-1a and HIF-2a for degradation by the ubiquitin–…”
BackgroundTET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling
Zhang, X., Li, S., He, J., Jin, Y., Zhang, R., Dong, W., Lin, M., Yang, Y., Tian, T., Zhou, Y., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3013 · Cited by 65
Hypoxia disrupts the expression levels of circadian rhythm genes in hepatocellular carcinoma
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“…of the proline residues by prolyl hydroxylase domain protein 2 promotes the interaction of HIF-1 α and HIF-2 α with the von-Hippel-Lindau tumor suppressor protein, which recruits E3 ubiquitin-protein ligase, targetingHIF-1 α and HIF-2 α for degradation by the ubiquitin-proteasome system (35).”
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“Because of this instability and the low abundance of HIFs, biochemical studies often require extraordinary numbers of cells, which is challenging for hypoxia disease relevant cell types outside of cancer cell lines.”
BackgroundInfluentialThe HILDA Complex Coordinates a Conditional Switch in the 3′-Untranslated Region of the VEGFA mRNA
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“In normoxia, O2dependent prolyl hydroxylation of HIF-1a triggers recognition by VHL and consequent degradation, thereby inhibiting expression of HIF-1a targets [40].”
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“This nucleolar capture inactivates VHL, which normally mediates degradation of the transcription factor HIF which is involved in stress adaptation [97].”
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“In the presence of oxygen, HIF-α subunits are 19 hydroxylated at two conserved prolines by prolyl-hydroxylases (PHD), leading to 20 recognition and ubiquitination by the Von Hippel-Lindau (VHL) protein and resulting in 21 proteasomal degradation (13,14).”
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“The von Hippel-Lindau tumor suppressor (VHL) is an E3 Ubiquitin Ligase Which Ubiquitylates and targets the αsubunit of HIFs for oxygen-dependent proteolysis (Haase, 2009).”
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BackgroundInfluentialElse, T., Jonasch, E. W., Iliopoulos, O., Beckermann, K. E., Narayan, V., Maughan, B. L., Oudard, S. M., Maranchie, J. K., Iversen, A. B. B., Goldberg, C. M., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-2592 · Cited by 33
“Von Hippel – Lindau (VHL) disease is a genetic disorder characterized by the inactivation of the VHL tumor-suppressor gene and the formation of multiple multisystemic benign and malignant tumors (1, 2).”
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“The pVHL is a tumor suppressor and substraterecognition component of the E3 ubiquitin ligase complex that in normoxic conditions, will ubiquitinate hydroxylated HIF-1α leading to its subsequent degradation [95].”
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“VHL is a tumor suppressor gene that acts as an E3 ubiquitin ligase and induces HIF-1 a degradation [96].”
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“Post-therapy tumors of HPD patients show somatic mutations in the von Hippel–Lindau tumor suppressor gene (VHL), which is a master regulator of HIF activity [113,226].”
BackgroundBelzutifan (MK-6482): Biology and Clinical Development in Solid Tumors
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Dimethyl fumarate inhibits the expression and function of hypoxia-inducible factor-1α (HIF-1α)
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“EPAS1 2034 Hypoxia-inducible factor 2-alpha (HIF2α) Transcriptional activation of EPO [17] HIF1A 3091 Hypoxia-inducible factor 1-alpha (HIF1α) Transcriptional activation [16] HIF3A 64344 Hypoxia-inducible factor 3-alpha (HIF3α) Transcriptional repression [16] EGLN1 54583 HIF-prolyl hydroxylase 2 (PHD2) HIF2α hydroxyla…”
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“HIF1α, a protein with particularly high turnover [22], was detected to control proteasome inhibition.”
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“The hydroxylation of these two proline residues lead to the binding of the von Hippel–Lindau tumor suppressor protein (pVHL), the substrate recognition component of an E3 ubiquitin ligase, to the HIF-1α protein (Haase, 2009).”
BackgroundLiu, D., & Li, H. (2019) · Bioscience Reports · doi:10.1042/bsr20181650 · Cited by 23
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Role of Hypoxia-Inducible Factors in Acute Kidney Injury
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Tivozanib for the treatment of renal cell carcinoma
Santoni, M., Massari, F., Piva, F., Carrozza, F., Nunno, V. D., Cimadamore, A., Martignetti, A., Montironi, R., & Battelli, N. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1480722 · Cited by 22
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Tacelli, M., Gentiluomo, M., Biamonte, P., Castano, J. P., Berković, M. C., Cives, M., Kapitanović, S., Marinoni, I., Marinović, S., Nikas, I. P., et al. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.03.005 · Cited by 23
The link between obesity and aging - insights into cardiac energy metabolism
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“A rapid activation of HIF-1 is due to a blockage of the ubiquitin-mediated proteasomal degradation in the absence of oxygen (Huang et al., 1996; Haase, 2009) and later on to an increase in HIF-1α mRNA expression and subsequent alterations in protein”
BackgroundCD105 in the progression and therapy of renal cell carcinoma
Oladejo, M., Nguyen, H.-M., & Wood, L. M. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216327 · Cited by 20
The Janus face of HIF-1α in ischemic stroke and the possible associated pathways
Amin, N., Abbasi, I. N., Wu, F., Shi, Z., Sundus, J., Badry, A., Yuan, X., Zhao, B., Pan, J., Mi, X., et al. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105747 · Cited by 23
Targeting the prostate tumor microenvironment by plant-derived natural products
Wu, J., Ji, H., Li, T., Guo, H., Xu, H., Zhu, J., Tian, J., Gao, M., Wang, X., & Zhang, A. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.111011 · Cited by 21
Using a yeast two-hybrid system to identify FTCD as a new regulator for HIF-1α in HepG2 cells
Yu, Z., Ge, Y., Xie, L., Zhang, T., Huang, L., Zhao, X., Liu, J., & Huang, G. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.03.016 · Cited by 19
Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities
Awan, A. B., Osman, M. J. A., & Khan, O. M. (2025) · Cells · doi:10.3390/cells14020069 · Cited by 18
Metabolic Alterations at the Crossroad of Aging and Oncogenesis
Raffaghello, L., & Longo, V. D. (2017) · International review of cytology · doi:10.1016/bs.ircmb.2017.01.003 · Cited by 19
“Specifically, sirtuin 1 deacetylases HIF-1α and promotes its interaction with the ubiquitin ligase VHL which leads to the degradation of HIF-1α (Gomes et al., 2013; Haase, 2009).”
BackgroundCorrelation analysis of VHL and Jade-1 gene expression in human renal cell carcinoma
Xiao-fen, W., Ting, C., Li, J., Deng-yang, M., Zhu, Q., & Xin, L. (2016) · Open Medicine · doi:10.1515/med-2016-0043 · Cited by 17
“The best-characterized function of VHL refers to targeting of the hypoxia-inducible factor (HIF) transcription factor for proteolytic degradation [9,10].”
BackgroundVon Hippel-Lindau syndrome: clinical features, genetic foundations, and management strategies
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Rana, H. Q., Koeller, D. R., Schwartz, A., Manning, D. K., Schneider, K. A., Krajewski, K. M., Choueiri, T. K., Lindeman, N. I., Garber, J. E., & Ghazani, A. A. (2021) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2021.104359 · Cited by 16
TCF3 regulates human endometrial stromal cell proliferation and migration in RPL
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Expression and significance of HIF-1α and HIF-2α in pancreatic cancer
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“Subsequently, VHL recruits additional proteins, including elon-gin C, elongin B, cullin-2 and Rbx 1 to form the VCB-Cul2 E3 ligase complex [56–58].”
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“, in tumors), stabilization of HIF1α and HIF2α (encoded by EPAS1) occurs, which is what results in induction of transcription of many genes encoding proteins involved in angiogenesis [70].”
BackgroundRole of Biomarkers in Prediction of Response to Therapeutics in Metastatic Renal-Cell Carcinoma
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Zeng, H., Chen, L., Huang, Y., Luo, Y., & Ma, X. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.553099 · Cited by 17
“Among them, the overexpression of vascular epithelial growth factor (VEGF) can strongly induce angiogenesis in hypoxia environment of tumors, and are related with enhanced risk of death in HNSCC (Kyzas et al., 2005; Haase, 2009).”
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Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death
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“By contrast, under hypoxic conditions HiF-1 α acts as the primary transcription factor functioning to activate multiple target genes (10).”
TCEB2 confers resistance to VEGF-targeted therapy in ovarian cancer
Deng, Z., Zhou, J., Han, X., & Li, X. (2015) · Oncology Reports · doi:10.3892/or.2015.4388 · Cited by 14
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“HIF-1α regulates metabolic adaptation to hypoxia and activates multiple target genes, including vascular endothelial growth factor, erythropoietin and nuclear factor-κB under hypoxic conditions (4).”
BackgroundMEK2 Negatively Regulates Lipopolysaccharide-Mediated IL-1β Production through HIF-1α Expression
Talwar, H. S., Bouhamdan, M., Bauerfeld, C. P., Talreja, J., Aoidi, R., Houde, N., Charron, J., & Samavati, L. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801477 · Cited by 14
“Mutations in pVHL and loss of its function may lead to HIF-1a accumulation and give rise to various cancers (15).”
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The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain
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“Hereinafter, the complex binds hypoxia response elements (HRE) and further induces transcription [93].”
BackgroundThe Protective Role of pVHL in Imiquimod-Induced Psoriasis-like Skin Inflammation
Martínez-Torres, I., Tepale-Segura, A., Castro-Escamilla, O., Cancino‐Díaz, J. C., Rodríguez–Martínez, S., Pérez‐Tapia, S. M., Bonifaz, L. C., & Cancino-Diaz, M. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095226 · Cited by 11
“The von Hippel–Lindau protein is a tumor suppressor gene involved in the negative regulation of HIF-1α in normoxic conditions, whereas mutations on the VHL gene or hypoxic conditions prevent HIF-1α degradation, which promotes the expression of angiogenic and inflammatory mediators [16].”
BackgroundTarget therapy in metastatic pheochromocytoma: current perspectives and controversies
Mohammed, A. A., Elshentenawy, A., Sherisher, M. A., & EL-Khatib, H. M. (2014) · Oncology Reviews · doi:10.4081/oncol.2014.249 · Cited by 11
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“Hydroxylated HIF-α binds to the Von Hippel-Lindau tumor suppressor and is rapidly degraded via a ubiquitin-proteasome pathway (6).”
Scharping, N. E., Ge, X., Matias, M. I., Jiang, F., Cafferata, A., Heeg, M., Monell, A., Galletti, G., Cheung, K. P., Rock, A. E., et al. (2025) · Cell · doi:10.1016/j.cell.2026.02.019 · Cited by 12
Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy
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EDDM3A drives gastric cancer progression by promoting HIF-1α-dependent aerobic glycolysis
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“It has been well-known that HIF-1α is hydroxylated and subsequently degraded by the E3 ubiquitin ligase Von Hippel–Lindau (VHL) in normoxia condition [10, 11].”
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Metadata
- Authors
- Haase, V.
- Affiliations
- Vanderbilt University Medical Center (US)
- Corresponding author
- Haase, Volker
- ORCID
- Haase, Volker
- Venue
- Current Pharmaceutical Design
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2009-11-01
- Volume
- 15
- Issue
- 33
- Pages
- 3895-3903
- ISSN
- 1381-6128 (ISSN-L)
- PMC
- PMC3622710
- OpenAlex
- W2067955850
- Cited by
- 175
- References
- 114
- Citations by year
- 2026: 5 · 2025: 27 · 2024: 19 · 2023: 21 · 2022: 20 · 2021: 18 · 2020: 10 · 2019: 9 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 5
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Current Pharmaceutical Design (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA100787)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080821, R01DK081646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- von Hippel-Lindau tumor suppressor, hypoxia-inducible factor, ubiquitin ligase, proteasomal degradation, oxygen sensing, hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, erythrocytosis, HIF-targeted therapy
- MeSH terms
- Animals, Humans, Mutation, Phenotype, Drug Delivery Systems, Gene Targeting, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination
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