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Updated: Apr 30, 2026
Inducible and Reversible Dominant-negative DN Protein Inhibition
Published on: January 7, 2019
Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein
Zhiyong Ding1, Peter German1, Shanshan Bai1
1Authors' Affiliations: Departments of Systems Biology, Genitourinary Medical Oncology, and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California.
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.
Insights
Aberrant von Hippel Lindau (VHL) protein function drives VHL-related diseases. Stabilizing VHL-R167Q protein levels with existing drugs shows promise for treating clear cell renal cell carcinoma (ccRCC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Von Hippel Lindau (VHL) protein dysfunction underlies VHL-related diseases, including clear cell renal cell carcinoma (ccRCC).
- Missense point mutations, like VHL-R167Q, are common in VHL disease, but their precise role in tumorigenesis and VHL protein function remains debated.
- Current therapeutic strategies do not specifically target VHL missense mutations.
Purpose of the Study:
- To investigate the proteostasis and function of the VHL-R167Q mutant under varying oxygen conditions and in a xenograft model.
- To elucidate the mechanism by which VHL-R167Q contributes to tumorigenesis.
- To identify potential therapeutic strategies for VHL-R167Q-associated diseases.
Main Methods:
- Analysis of VHL-R167Q protein levels and function under normoxia and hypoxia.
- Assessment of VHL-R167Q interaction with elongin B and C.
- Evaluation of tumor suppression in a xenograft mouse model.
- In silico analysis to identify other potentially targetable VHL mutants.
Main Results:
- VHL-R167Q protein levels directly correlate with its capacity to downregulate hypoxia-inducible factor 2α (HIF2α) and inhibit tumor growth.
- Proteasome inhibitors (bortezomib, carfilzomib) stabilize VHL-R167Q, enhancing its HIF2α downregulation.
- VHL-R167Q exhibits reduced binding affinity to elongin B/C but retains partial complex formation and tumor suppressive function, which can be restored by increasing VHL-R167Q levels.
- Identification of other missense VHL mutants amenable to similar therapeutic rescue strategies.
Conclusions:
- VHL-R167Q's tumor suppressive ability is contingent on its protein levels.
- Stabilizing VHL-R167Q using existing proteasome inhibitors represents a viable therapeutic approach for ccRCC and other VHL-related diseases.
- This study provides a mechanistic understanding of VHL-R167Q in tumorigenesis and offers a targeted therapeutic avenue for patients with specific VHL mutations.
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