| First Author | Cheng J | Year | 2007 |
| Journal | Cell | Volume | 131 |
| Issue | 3 | Pages | 584-95 |
| PubMed ID | 17981124 | Mgi Jnum | J:141453 |
| Mgi Id | MGI:3818351 | Doi | 10.1016/j.cell.2007.08.045 |
| Citation | Cheng J, et al. (2007) SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131(3):584-95 |
| abstractText | 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. |
