SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity

Biochem Biophys Res Commun. 2007 Aug 31;360(3):646-52. doi: 10.1016/j.bbrc.2007.06.103. Epub 2007 Jun 27.


The hypoxic response of mammalian cells is controlled through a transcriptional pathway that is mediated by the hypoxia-inducible factor (HIF). Here, we show that HIF-1alpha undergoes post-translational modification by the three isoforms of the small ubiquitin-related modifier (SUMO-1, -2 and -3) in vitro in proximity to and within the oxygen-dependent degradation domain (ODDD). SUMO conjugation is promoted in vitro by the E3 SUMO ligase RanBP2/Nup538 and SUMO modification in vivo does not change HIF-1alpha turnover rate. Using cotransfection of siRNA targeted to endogenous HIF-1alpha together with HIF-1alpha siRNA-resistant expression vectors carrying mutations for SUMO modification we demonstrate increased hypoxia-response element-dependent transcriptional activity for SUMO-deficient HIF-1alpha. These results indicate that when HIF-1alpha is conjugated to SUMO its transcriptional activity is decreased and that this is not mediated by a change in the protein's half-life.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Down-Regulation / drug effects
  • Glutathione Transferase / genetics
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mutagenesis, Site-Directed
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Transcription, Genetic / drug effects


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • SUMO-1 Protein
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Glutathione Transferase