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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2003-4-28
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pubmed:abstractText |
The hypoxia-inducible factor (HIF) activates the expression of genes that contain a hypoxia response element. The alpha-subunits of the HIF transcription factors are degraded by proteasomal pathways during normoxia but are stabilized under hypoxic conditions. The von Hippel-Lindau protein (pVHL) mediates the ubiquitination and rapid degradation of HIF-alpha (including HIF-1alpha and HIF-2alpha). Post-translational hydroxylation of a proline residue in the oxygen-dependent degradation (ODD) domain of HIF-alpha is required for the interaction between HIF and VHL. It has previously been established that cobalt mimics hypoxia and causes accumulation of HIF-1alpha and HIF-2alpha. However, little is known about the mechanism by which this occurs. In an earlier study, we demonstrated that cobalt binds directly to the ODD domain of HIF-2alpha. Here we provide the first evidence that cobalt inhibits pVHL binding to HIF-alpha even when HIF-alpha is hydroxylated. Deletion of 17 amino acids within the ODD domain of HIF-2alpha that are required for pVHL binding prevented the binding of cobalt and stabilized HIF-2alpha during normoxia. These findings show that cobalt mimics hypoxia, at least in part, by occupying the VHL-binding domain of HIF-alpha and thereby preventing the degradation of HIF-alpha.
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pubmed:grant |
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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/Cobalt,
http://linkedlifedata.com/resource/pubmed/chemical/Deferoxamine,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoxia-Inducible Factor 1, alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Ligases,
http://linkedlifedata.com/resource/pubmed/chemical/PC 12,
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/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 |
May
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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 |
2
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
15911-6
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:12606543-Amino Acid Sequence,
pubmed-meshheading:12606543-Animals,
pubmed-meshheading:12606543-Basic Helix-Loop-Helix Transcription Factors,
pubmed-meshheading:12606543-CHO Cells,
pubmed-meshheading:12606543-Cobalt,
pubmed-meshheading:12606543-Cricetinae,
pubmed-meshheading:12606543-Deferoxamine,
pubmed-meshheading:12606543-Glycine,
pubmed-meshheading:12606543-Hydroxylation,
pubmed-meshheading:12606543-Hypoxia-Inducible Factor 1, alpha Subunit,
pubmed-meshheading:12606543-Ligases,
pubmed-meshheading:12606543-Molecular Sequence Data,
pubmed-meshheading:12606543-Rats,
pubmed-meshheading:12606543-Trans-Activators,
pubmed-meshheading:12606543-Transcription Factors,
pubmed-meshheading:12606543-Tumor Suppressor Proteins,
pubmed-meshheading:12606543-Ubiquitin-Protein Ligases,
pubmed-meshheading:12606543-Von Hippel-Lindau Tumor Suppressor Protein
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pubmed:year |
2003
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pubmed:articleTitle |
Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha.
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pubmed:affiliation |
Genome Research Institute, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0505, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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