Renal cell carcinoma risk in type 2 von Hippel–Lindau disease correlates with defects in pVHL stability and HIF-1α interactions
- 31 October 2005
- journal article
- research article
- Published by Springer Nature in Oncogene
- Vol. 25 (3) , 370-377
- https://doi.org/10.1038/sj.onc.1209062
Abstract
The von Hippel–Lindau (VHL) tumor suppressor protein is the substrate binding subunit of the CBCVHL E3 ubiquitin ligase complex. Mutations in the VHL gene cause a variety of tumors with complex genotype/phenotype correlations. Type 2A and type 2B VHL disease are characterized by a low or high risk of renal cell carcinoma, respectively. To investigate the molecular basis underlying the difference between disease types 2A and 2B, we performed a detailed biochemical analysis of the two most frequent type 2A mutations, Y98 H and Y112 H, in comparison to type 2B mutations in the same residues, Y98N and Y112N. While none of these mutations affected the assembly of CBCVHL complexes, the type 2A mutant proteins exhibited higher stabilities at physiological temperature. Moreover, the type 2A mutant proteins possessed higher binding affinities for the key cellular substrate, hypoxia-inducible transcription factor 1 (HIF-1α). Consistent with these results, type 2A but not type 2B mutant VHL proteins retained significant ubiquitin ligase activity towards HIF-1α in vitro. We propose that this residual ubiquitin ligase activity is sufficient to suppress renal cell carcinogenesis in vivo.Keywords
This publication has 41 references indexed in Scilit:
- A Conserved Family of Prolyl-4-Hydroxylases That Modify HIFScience, 2001
- Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau diseaseHuman Molecular Genetics, 2001
- Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor ProteinJournal of Biological Chemistry, 2000
- Functional Defects of the DnaK756 Mutant Chaperone ofEscherichia coli Indicate Distinct Roles for Amino- and Carboxyl-terminal Residues in Substrate and Co-chaperone Interaction and Interdomain CommunicationJournal of Biological Chemistry, 1999
- Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL geneAmerican Journal of Medical Genetics, 1999
- Baseline length and automated fitting of denaturation dataProtein Science, 1998
- Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A.Journal of Medical Genetics, 1996
- Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effectHuman Genetics, 1995
- Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: Correlations with phenotypeHuman Mutation, 1995
- Engineered disulfide bonds as probes of the folding pathway of barnase: Increasing the stability of proteins against the rate of denaturationBiochemistry, 1993