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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
33
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pubmed:dateCreated |
2000-9-21
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Basic Helix-Loop-Helix...,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Hif1a protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Ligases,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oxygen,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitins,
http://linkedlifedata.com/resource/pubmed/chemical/Von Hippel-Lindau Tumor Suppressor...,
http://linkedlifedata.com/resource/pubmed/chemical/endothelial PAS domain-containing...
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
275
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
25733-41
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pubmed:dateRevised |
2007-4-11
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pubmed:meshHeading |
pubmed-meshheading:10823831-Animals,
pubmed-meshheading:10823831-Basic Helix-Loop-Helix Transcription Factors,
pubmed-meshheading:10823831-COS Cells,
pubmed-meshheading:10823831-Cysteine Endopeptidases,
pubmed-meshheading:10823831-DNA-Binding Proteins,
pubmed-meshheading:10823831-Hypoxia-Inducible Factor 1,
pubmed-meshheading:10823831-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:10823831-Immunoblotting,
pubmed-meshheading:10823831-Ligases,
pubmed-meshheading:10823831-Multienzyme Complexes,
pubmed-meshheading:10823831-Mutagenesis, Site-Directed,
pubmed-meshheading:10823831-Mutation, Missense,
pubmed-meshheading:10823831-Nuclear Proteins,
pubmed-meshheading:10823831-Oxygen,
pubmed-meshheading:10823831-Plasmids,
pubmed-meshheading:10823831-Precipitin Tests,
pubmed-meshheading:10823831-Proteasome Endopeptidase Complex,
pubmed-meshheading:10823831-Protein Binding,
pubmed-meshheading:10823831-Protein Biosynthesis,
pubmed-meshheading:10823831-Protein Structure, Tertiary,
pubmed-meshheading:10823831-Proteins,
pubmed-meshheading:10823831-Rats,
pubmed-meshheading:10823831-Reticulocytes,
pubmed-meshheading:10823831-Substrate Specificity,
pubmed-meshheading:10823831-Time Factors,
pubmed-meshheading:10823831-Trans-Activators,
pubmed-meshheading:10823831-Transcription Factors,
pubmed-meshheading:10823831-Transfection,
pubmed-meshheading:10823831-Tumor Suppressor Proteins,
pubmed-meshheading:10823831-Ubiquitin-Protein Ligases,
pubmed-meshheading:10823831-Ubiquitins,
pubmed-meshheading:10823831-Von Hippel-Lindau Tumor Suppressor Protein
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pubmed:year |
2000
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pubmed:articleTitle |
Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.
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pubmed:affiliation |
Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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