title: Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein.
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.
authors.affiliation: Authors' 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.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Authors' 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.
authors.forename: Peter
authors.initials: P
authors.lastname: German
authors.affiliation: Authors' 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.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Bai
authors.affiliation: Authors' 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.
authors.forename: A Srinivas
authors.initials: AS
authors.lastname: Reddy
authors.affiliation: Authors' 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.
authors.forename: Xian-De
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Authors' 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.
authors.forename: Mianen
authors.initials: M
authors.lastname: Sun
authors.affiliation: Authors' 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.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Authors' 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.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Authors' 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.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Authors' 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.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.affiliation: Authors' 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.
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Authors' 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.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Authors' 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 ejonasch@mdanderson.org.
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D000075065:Elongin; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000235:genetics*; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000075065:Elongin; D050505:Mutant Proteins; D046988:Proteasome Endopeptidase Complex; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C000616396:ELOB protein, human; C000616395:ELOC protein, human; C000616401:Elob protein, mouse; C000616411:Eloc protein, mouse; C497446:VHL protein, human
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