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Abstract
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.