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SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.

Cell | Nov 2, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17981124

SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.

Pubmed ID: 17981124 RIS Download

Mesh terms: Anemia | Animals | Apoptosis | Cell Hypoxia | Embryo, Mammalian | Endopeptidases | Erythroid Precursor Cells | Erythropoiesis | Erythropoietin | Fetus | Hypoxia-Inducible Factor 1, alpha Subunit | Liver | Mice | Mice, Knockout | Models, Biological | Proteasome Endopeptidase Complex | Protein Binding | Protein Processing, Post-Translational | Signal Transduction | Thermodynamics | Transcription, Genetic | Von Hippel-Lindau Tumor Suppressor Protein

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Associated grants

  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: R01 CA080089
  • Agency: NCI NIH HHS, Id: R01 CA080089-01A1
  • Agency: NCI NIH HHS, Id: R01 CA080089-02
  • Agency: NCI NIH HHS, Id: R01 CA080089-03
  • Agency: NCI NIH HHS, Id: R01 CA080089-04
  • Agency: NCI NIH HHS, Id: R01 CA080089-05
  • Agency: NCI NIH HHS, Id: R01 CA139520
  • Agency: NCI NIH HHS, Id: R01 CA80089

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