title: VHL type 2B mutations retain VBC complex form and function.
abstract: BACKGROUND
  von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1alpha and HIF-2alpha), resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease.
  
  
  RESULTS
  This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1alpha.
  
  
  CONCLUSIONS
  Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition for cancer development in VHL disease.
authors.affiliation: Department of Medicine, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Durham, North Carolina, United States of America.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hacker
authors.forename: Caroline Martz
authors.initials: CM
authors.lastname: Lee
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D000075065:Elongin; D020022:Genetic Predisposition to Disease; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020125:Mutation, Missense / Q000502:physiology*; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000075065:Elongin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C000616395:ELOC protein, human; C497442:HIF1A protein, human; C497446:VHL protein, human