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Conjugation of small ubiquitin-related modifier proteins (SUMO) to form larger substrates has been implicated in the regulation of multiple cellular processes in mammals including transcription, cell signalling and cancer progression. This conjugation is a dynamic process that can be reversed by a family of Sentrin/SUMO-specific proteases (SENPs).
This study investigated the physiological consequences of SUMOylation and deSUMOylation with particular regard to hypoxia-inducible factor 1α (HIF1α) and SENP1. A series of experiments were undertaken using SENP1 (a nuclear SUMO protease) knockout mice (SENP1−/−). SENP1 was chosen as earlier studies implicated SENP1 mutations in early fetal death in mice and SENP1 is found in humans.
By comparing SENP1−/− and SENP1 wild-type mice (SENP1−/+), it was established that mid gestation fetal death occurred secondary to severe fetal anaemia because of deficient erythropoietin production. Erythropoietin production was subsequently linked with the stability of HIF1α, a process that was directly influenced by the presence of SENP1. Hypoxia-induced SUMOylation and subsequent degradation of HIF1α is increased in SENP1−/− mice compared with wild-type mice, which suggests that SENP1 is essential to prevent degradation of HIF1α in response to hypoxia. Further experimentation showed that the degradation of HIF1α was through a Von Hippel-Lindau and ubiquitin/proteasome dependent mechanism.
This study highlights the important biological consequences that SUMOylation and deSUMOylation can have in mammals. In particular, the presence of SENP1 is essential to stabilise HIF1α in response to hypoxia for prevention of early fetal death in mice. The study does not identify why hypoxia causes SUMOylation of HIF1α and further studies are required to establish the nature of this.
Cheng J, Kang X, Zhang S, et al. SUMO-specific protease 1 is essential for stabilisation of HIF1α during hypoxia. Cell 2007;131:584–95
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