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.
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
Cell
Date: Nov. 02, 2007
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