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10.1074/jbc.M300463200

http://scihub22266oqcxt.onion/10.1074/jbc.M300463200
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12606543!ä!12606543

suck abstract from ncbi


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pmid12606543      J+Biol+Chem 2003 ; 278 (18): 15911-6
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  • Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha #MMPMID12606543
  • Yuan Y; Hilliard G; Ferguson T; Millhorn DE
  • J Biol Chem 2003[May]; 278 (18): 15911-6 PMID12606543show ga
  • 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.
  • |*Tumor Suppressor Proteins[MESH]
  • |*Ubiquitin-Protein Ligases[MESH]
  • |Amino Acid Sequence[MESH]
  • |Animals[MESH]
  • |Basic Helix-Loop-Helix Transcription Factors[MESH]
  • |CHO Cells[MESH]
  • |Cobalt/*pharmacology[MESH]
  • |Cricetinae[MESH]
  • |Deferoxamine/pharmacology[MESH]
  • |Glycine/*analogs & derivatives[MESH]
  • |Hydroxylation[MESH]
  • |Hypoxia-Inducible Factor 1, alpha Subunit[MESH]
  • |Ligases/*metabolism[MESH]
  • |Molecular Sequence Data[MESH]
  • |Rats[MESH]
  • |Trans-Activators/chemistry/*metabolism[MESH]
  • |Transcription Factors/*metabolism[MESH]


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