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

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

Authors

  • Cheng J
  • Kang X
  • Zhang S
  • Yeh ET

Journal

Cell

Publication Data

November 2, 2007

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

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