Insights into the Role of the von Hippel-Lindau Gene Product

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Abstract

Many adaptive responses to hypoxia involve changes in gene transcription mediated by the hypoxia-inducible factor 1 complex. Central to this is oxygen-dependent proteolysis of the α subunit, which has recently been shown to require the von Hippel-Lindau tumour-suppressor protein. This observation provides one mechanism by which inherited defects in the von Hippel-Lindau gene could cause features of the clinical syndrome, and offers insight into the events leading to sporadic clear cell renal cancer. Furthermore, it clearly implicates the von Hippel-Lindau tumour-suppressor protein in the biochemistry of oxygen sensing.

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Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.

M Ohh, C. Park, M Ivan … (2000)

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.

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Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.

M E Cockman, N Masson, D R Mole … (2000)

The von Hippel-Lindau tumor suppressor protein (pVHL) has emerged as a key factor in cellular responses to oxygen availability, being required for the oxygen-dependent proteolysis of alpha subunits of hypoxia inducible factor-1 (HIF). Mutations in VHL cause a hereditary cancer syndrome associated with dysregulated angiogenesis, and up-regulation of hypoxia inducible genes. Here we investigate the mechanisms underlying these processes and show that extracts from VHL-deficient renal carcinoma cells have a defect in HIF-alpha ubiquitylation activity which is complemented by exogenous pVHL. This defect was specific for HIF-alpha among a range of substrates tested. Furthermore, HIF-alpha subunits were the only pVHL-associated proteasomal substrates identified by comparison of metabolically labeled anti-pVHL immunoprecipitates from proteosomally inhibited cells and normal cells. Analysis of pVHL/HIF-alpha interactions defined short sequences of conserved residues within the internal transactivation domains of HIF-alpha molecules sufficient for recognition by pVHL. In contrast, while full-length pVHL and the p19 variant interact with HIF-alpha, the association was abrogated by further N-terminal and C-terminal truncations. The interaction was also disrupted by tumor-associated mutations in the beta-domain of pVHL and loss of interaction was associated with defective HIF-alpha ubiquitylation and regulation, defining a mechanism by which these mutations generate a constitutively hypoxic pattern of gene expression promoting angiogenesis. The findings indicate that pVHL regulates HIF-alpha proteolysis by acting as the recognition component of a ubiquitin ligase complex, and support a model in which its beta domain interacts with short recognition sequences in HIF-alpha subunits.

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Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.

C Stebbins, W G Kaelin, N. Pavletich (1999)

Mutation of the VHL tumor suppressor is associated with the inherited von Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible proteins. The structure of the ternary complex at 2.7 angstrom resolution shows two interfaces, one between VHL and ElonginC and another between ElonginC and ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL responsible for ElonginC binding. A mutational patch on a separate domain of VHL indicates a second macromolecular binding site. The structure extends the similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins for degradation, supporting the hypothesis that VHL may function in an analogous pathway.

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Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2001

Publication date (Print): 2001

Publication date (Electronic): 27 June 2001

Volume: 9

Issue: 4

Pages: 235-240

Affiliations

Nephrology and Oxygen-Sensing Laboratory, Henry Wellcome Building of Genomic Medicine, Oxford, UK

Article

Publisher ID: 52617 Other ID: Exp Nephrol 2001;9:235–240

DOI: 10.1159/000052617

PubMed ID: 11423722

SO-VID: c8fdba82-b4e7-4c63-93e5-dcb3e84d750c

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Insights into the Role of the von Hippel-Lindau Gene Product

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Abstract

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Karger: Nephrology

Most cited references 8

Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.

Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.

Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.

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