The DOI matches its Crossref record; 119 of the 119 references it cites were found in a registry or an index.
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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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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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
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
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
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
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
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
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 · cited 1×
“They regulate gene expression by binding to hypoxia-response elements (HREs), specific DNA recognition sequences located in hypoxia enhancer containing regulatory regions of HIF target genes, and consist of an oxygen-sensitive αsubunit and a constitutively expressed β-subunit, also known as the arylhydrocarbon recepto…”
BackgroundMutations of the VHL tumour suppressor gene in renal carcinoma
Gnarra, J. R., Tory, K., Weng, Y., Schmidt, L., Wei, M. H., Li, H., Latif, F., Liu, S., Chen, F., Duh, F.-M., et al. (1994) · Nature Genetics · doi:10.1038/ng0594-85 · Cited by 1,730
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Lonser, R. R., Glenn, G. M., Walther, M. M., Chew, E. Y., Libutti, S. K., Linehan, W. M., & Oldfield, E. H. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13643-4 · Cited by 1,630
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Jonasch, E., Donskov, F., Iliopoulos, O., Rathmell, W. K., Narayan, V. K., Maughan, B. L., Oudard, S., Else, T., Maranchie, J. K., Welsh, S. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103425 · Cited by 714
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CD8+ T cell metabolism in infection and cancer
Reina‐Campos, M., Scharping, N. E., & Goldrath, A. W. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00537-8 · Cited by 657
Clinical update on cancer: molecular oncology of head and neck cancer
Suh, Y., Amelio, I., Urbano, T. G., & Tavassoli, M. (2014) · Cell Death and Disease · doi:10.1038/cddis.2013.548 · Cited by 195
The Impact of Hypoxia in Early Pregnancy on Placental Cells
Zhao, H. F., Wong, R. J., & Stevenson, D. K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189675 · Cited by 190
“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].”
BackgroundPeña, C. E., Lathia, C. D., Shan, M., Escudier, B. J., & Bukowski, R. M. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3343 · Cited by 178
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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