VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL

Knauth, Katja; Cartwright, Edward; Freund, Stefan; Bycroft, Mark; Buchberger, Alexander

doi:10.1074/jbc.m809056200

Cited by 21 publications

(25 citation statements)

References 55 publications

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“…Consistent with the efficient binding of the VHL30 P81S mutant with VHL E3 ligase components, expression of this mutant in VHL-null 786-O cells resulted in a dramatic decrease in the level of HIF-2α, which was similar to that achieved by wild-type VHL30 (Figure 5). Degradation of HIF-1α by VHL P81S mutant was also demonstrated by Knauth et al, who used P81S mutation in VHL19, a shorter VHL isoform encoding amino acid 54–213 [29]. These results indicate that the renal carcinoma-associated VHL P81S mutant displays reduced HP1 binding, yet retains the ability to degrade HIF-α.…”

Section: Resultssupporting

confidence: 56%

The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

Lai

Song

Hakala

et al. 2012

Archives of Biochemistry and Biophysics

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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor is associated with renal carcinoma, hemangioblastoma and pheochromocytoma. The VHL protein is a component of a ubiquitin ligase complex that ubiquitinates and degrades hypoxia inducible factor-α (HIF-α). Degradation of HIF-α by VHL is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in tumor suppression and other biological processes. Using GST-VHL pull-down experiment and mass spectrometry, we detected an interaction between VHL and heterochromatin protein 1 (HP1). We identified a conserved HP1-binding motif (PXVXL) in the β domain of VHL, which is disrupted in a renal carcinoma-associated P81S mutant. We show that the VHL P81S mutant displays reduced binding to HP1, yet retains the ability to interact with elongin B, elongin C, and cullin 2 and is fully capable of degrading HIF-α. We also demonstrate that HP1 increases the chromatin association of VHL. These results suggest a role for the VHL-HP1 interaction in VHL chromatin targeting.

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Section: Resultssupporting

confidence: 56%

The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

Lai

Song

Hakala

et al. 2012

Archives of Biochemistry and Biophysics

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“…Recently, Type 2C-associated mutations were found to cause structural changes in pVHL, in turn, causing ubiquitin ligase complex destabilization [Knauth et al, 2009]. These structural defects in pVHL were thought to affect HIF-dependent and -independent regulation, and thus could be involved in pheochromocytoma development [Knauth et al, 2009]. However, other studies have found Type 2C mutations capable of normal HIF suppression and believe that this is why VHL Type 2C patients have a low risk of developing hemangioblastomas and RCC Ohh et al, 2000].…”

Section: Pheochromocytomas Associated With Vhl Diseasementioning

confidence: 94%

“…However, other studies have found Type 2C mutations capable of normal HIF suppression and believe that this is why VHL Type 2C patients have a low risk of developing hemangioblastomas and RCC Ohh et al, 2000]. Still others believe that this seemingly normal HIF regulation might be masked by overexpression of VHL in the specific cell lines used [Knauth et al, 2009]. Some have also theorized that the development of pheochromocytomas may be due to abnormal assembly of the extracellular fibronectin matrix .…”

Section: Pheochromocytomas Associated With Vhl Diseasementioning

confidence: 96%

Section: Pheochromocytomas Associated With Vhl Diseasementioning

confidence: 99%

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Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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“…The fact that p.Pro138Thr was detected in a subject with PH suggests that this core mutation does not cause complete protein unfolding and may be able to maintain interactions with pVHL partners. The latter has been demonstrated for other core mutations, reported as typically associated with VHL type 2C, for example, p.Leu188Val, and p.Val84Leu (Hoffman et al, 2001;Knauth et al, 2006;Grosfeld et al, 2007;Knauth et al, 2009). Furthermore, other previously described mutations altering the pVHL interface C between residues 114 and 154, such as p.Phe136Cys and p.Pro154Leu, have reduced ability to bind TBP1, necessary for proteasome binding (Fig.…”

Section: Considerations About Genotype-phenotype Correlationsmentioning

confidence: 90%

Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population

Leonardi

Martella

Tosatto

et al. 2011

Annals of Human Genetics

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SummaryMutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants.

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VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL

Cited by 21 publications

References 55 publications

The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

Genetic analysis of von Hippel-Lindau disease

Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population

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