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Cited by 1,050

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein

Open access
Cockman, Matthew E., Masson, Norma, Mole, David R., Jaakkola, Panu, Chang, Gin-Wen, Clifford, Steven C., Maher, Eamonn R., Pugh, Christopher W., Ratcliffe, Peter J., Maxwell, Patrick H.·2000·Journal of Biological Chemistry
DOI 10.1074/jbc.m002740200
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Abstract

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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Metadata

Authors
Cockman, M. E., Masson, N., Mole, D. R., Jaakkola, P., Chang, G.-W., Clifford, S. C., Maher, E. R., Pugh, C. W., Ratcliffe, P. J., & Maxwell, P. H.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2000-08
Volume
275
Issue
33
Pages
25733-25741
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m002740200
OpenAlex
W2080374319
Cited by
1,050
References
4
FWCI
30.31
Type
journal article
Language
en
Open access
hybrid

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