期刊
CELL
卷 131, 期 3, 页码 584-595出版社
CELL PRESS
DOI: 10.1016/j.cell.2007.08.045
关键词
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资金
- NCI NIH HHS [R01 CA080089-03, P30 CA016672, R01 CA080089-05, R01 CA139520, R01 CA080089-04, R01 CA080089, R01 CA080089-01A1, R01 CA80089, R01 CA080089-02, CA16672] Funding Source: Medline
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 1 alpha (HIF1 alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1a, 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 HIF1 alpha-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 HIF1a stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.
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