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SENP3 is responsible for HIF‐1 transactivation under mild oxidative stress via p300 de‐SUMOylation
Author(s) -
Huang Chao,
Han Yan,
Wang Yumei,
Sun Xuxu,
Yan Shan,
Yeh Edward T H,
Chen Yuying,
Cang Hui,
Li Hui,
Shi Guiying,
Cheng Jinke,
Tang Xueming,
Yi Jing
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.210
Subject(s) - sumo protein , transactivation , biology , oxidative stress , microbiology and biotechnology , genetics , biochemistry , gene , transcription factor , ubiquitin
The physiological function of Sentrin/SUMO‐specific proteases (SENPs) remains largely unexplored, and little is known about the regulation of SENPs themselves. Here, we show that a modest increase of reactive oxygen species (ROS) regulates SENP3 stability and localization. We found that SENP3 is continuously degraded through the ubiquitin‐proteasome pathway under basal condition and that ROS inhibit this degradation. Furthermore, ROS causes SENP3 to redistribute from the nucleoli to the nucleoplasm, allowing it to regulate nuclear events. The stabilization and redistribution of SENP3 correlate with an increase in the transcriptional activity of the hypoxia‐inducing factor‐1 (HIF‐1) under mild oxidative stress. ROS‐enhanced HIF‐1 transactivation is blocked by SENP3 knockdown. The de‐SUMOylating activity of SENP3 is required for ROS‐induced increase of HIF‐1 transactivation, but the true substrate of SENP3 is the co‐activator of HIF‐1α, p300, rather than HIF‐1α itself. Removing SUMO2/3 from p300 enhances its binding to HIF‐1α. In vivo nude mouse xenografts overexpressing SENP3 are more angiogenic. Taken together, our results identify SENP3 as a redox sensor that regulates HIF‐1 transcriptional activity under oxidative stress through the de‐SUMOylation of p300.