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SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia
Jinke Cheng,1,3 Xunlei Kang,2,3 Sui Zhang,1 and Edward T.H. Yeh1,2,
1 Department of Cardiology, the University of Texas M.D. Anderson Cancer Center, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA
2 Center for Cardiovascular Research, Brown Foundation Institute of Molecular Medicine, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA
3 Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, P. R. China
Corresponding author
Edward T.H. Yeh
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 1α (HIF1α) during hypoxia. Hypoxia induces SUMOylation of HIF1α, 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 HIF1α-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 HIF1α stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.
