ArticleCancer research2014
Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein.
Article in Cancer research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).Cancer metastasis reviews · 2026Review
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- The role of E3 ligases and deubiquitinases in PD-L1 regulation and the tumor microenvironment in renal cell carcinoma.Medical oncology (Northwood, London, England) · 2025Review
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
- Proteostasis Modulation in Germline Missense von Hippel Lindau Disease.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- VHL-P138R and VHL-L163R Novel Variants: Mechanisms of VHL Pathogenicity Involving HIF-Dependent and HIF-Independent Actions.Frontiers in endocrinology · 2022Article
- The Most CommonCancers · 2021Article
- Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery.Biomedicines · 2021Article
- Clear cell renal cell carcinoma ontogeny and mechanisms of lethality.Nature reviews. Nephrology · 2021Review
- The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation.PLoS genetics · 2020Article
- Deubiquitylase OTUD6B Governs pVHL Stability in an Enzyme-Independent Manner and Suppresses Hepatocellular Carcinoma Metastasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- Bexarotene - a novel modulator of AURKA and the primary cilium inJournal of cell science · 2018Article
- Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation.Case reports in endocrinology · 2018Article
- Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.Oncogene · 2017Article
- Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function.Oncogene · 2016Article
- USP9X destabilizes pVHL and promotes cell proliferation.Oncotarget · 2016Article
- Targeting tumor suppressor genes for cancer therapy.BioEssays : news and reviews in molecular, cellular and developmental biology · 2015Review
- The PI3K/AKT Pathway and Renal Cell Carcinoma.Journal of genetics and genomics = Yi chuan xue bao · 2015Review
- New strategies in renal cell carcinoma: targeting the genetic and metabolic basis of disease.Clinical cancer research : an official journal of the American Association for Cancer Research · 2015Article
- VHL, the story of a tumour suppressor gene.Nature reviews. Cancer · 2015Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.