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Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1 alpha interactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2006 (English)In: Oncogene, ISSN 0950-9232, Vol. 25, no 3, 370-377 p.Article in journal (Refereed) Published
Abstract [en]

The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate binding subunit of the CBC(VHL) 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 CBC(VHL) 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-1alpha). Consistent with these results, type 2A but not type 2B mutant VHL proteins retained significant ubiquitin ligase activity towards HIF-1alpha in vitro. We propose that this residual ubiquitin ligase activity is sufficient to suppress renal cell carcinogenesis in vivo.

Place, publisher, year, edition, pages
2006. Vol. 25, no 3, 370-377 p.
Keyword [en]
VHL, RCC, HIF-1 alpha
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-80297DOI: 10.1038/sj.onc.1209062PubMedID: 16261165OAI: oai:DiVA.org:uu-80297DiVA: diva2:108211
Available from: 2006-05-05 Created: 2006-05-05 Last updated: 2011-02-23Bibliographically approved

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Jemth, Per
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