Siah: new players in the cellular response to hypoxia

Cell Cycle. 2004 Nov;3(11):1345-7. doi: 10.4161/cc.3.11.1207. Epub 2004 Nov 6.


Prolyl-hydroxylation of HIF-1alpha is a prerequisite for pVHL binding to HIF-1alpha, which results in degradation of HIF-1alpha by the ubiquitin-proteasome pathway. Hydroxylation of HIF-1alpha is mediated by the family of prolyl-hydroxylase proteins (PHD). In hypoxia, HIF-1alpha is stabilized as a result of inhibition of HIF-1alpha hydroxylation, which in part is achieved by decreased activity of PHD enzymes at very low oxygen concentrations. We recently demonstrated that in hypoxia the stability of 2 of 3 PHDs (1 and 3) is regulated by the E3 ligases Siah1/2. Consequently, in hypoxia Siah determines the availability of PHD1/3, which otherwise modify HIF-1alpha to enable its association-dependent degradation by pVHL. These findings define a newly discovered layer in the regulation of HIF-1alpha in hypoxia. The roles of Siah activities in hypoxia responses are discussed.

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Immediate-Early Proteins / metabolism
  • Isoenzymes / metabolism
  • Mice
  • Mice, Knockout
  • Procollagen-Proline Dioxygenase / chemistry
  • Procollagen-Proline Dioxygenase / metabolism
  • Protein Processing, Post-Translational*
  • Proteins / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism


  • DNA-Binding Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immediate-Early Proteins
  • Isoenzymes
  • Proteins
  • Procollagen-Proline Dioxygenase
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Siah1a protein, mouse
  • Ubiquitin-Protein Ligases