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

0301 basic medicine 0303 health sciences Transcription, Genetic Recombinant Fusion Proteins SUMO-1 Protein Down-Regulation Hypoxia-Inducible Factor 1, alpha Subunit 3. Good health 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology Mutagenesis, Site-Directed Small Ubiquitin-Related Modifier Proteins Humans RNA, Small Interfering Glutathione Transferase HeLa Cells
DOI: 10.1016/j.bbrc.2007.06.103 Publication Date: 2007-06-28T09:03:25Z
ABSTRACT
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.
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