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The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death

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Leitao, B. B., Jones, M. C. and Brosens, Jan J. (2011) The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death. FASEB Journal, Vol.25 (No.10). pp. 3416-3425. doi:10.1096/fj.11-186346 ISSN 0892-6638.

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Official URL: http://dx.doi.org/10.1096/fj.11-186346

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Abstract

Human endometrial stromal cells (HESCs) exposed to reactive oxygen species (ROS) mount a hypersumoylation response in a c-Jun N-terminal kinase (JNK)-dependent manner. The mechanism that couples JNK signaling to the small ubiquitin-related modifier (SUMO) pathway and its functional consequences are not understood. We show that ROS-dependent JNK activation converges on the SUMO pathway via PIAS1 (protein inhibitor of activated STAT1). Unexpectedly, PIAS1 knockdown not only prevented ROS-dependent hypersumoylation but also enhanced JNK signaling in HESCs. Conversely, PIAS overexpression increased sumoylation of various substrates, including c-Jun, yet inhibited basal and ROS-dependent JNK activity independently of its SUMO ligase function. Expression profiling demonstrated that PIAS1 knockdown enhances and profoundly modifies the transcriptional response to oxidative stress signals. Using a cutoff of 2-fold change or more, a total of 250 ROS-sensitive genes were identified, 97 of which were not dependent on PIAS1. PIAS1 knockdown abolished the regulation of 43 genes but also sensitized 110 other genes to ROS. Importantly, PIAS1 silencing was obligatory for the induction of several cellular defense genes in response to oxidative stress. In agreement, PIAS1 knockdown attenuated ROS-dependent caspase-3/7 activation and subsequent apoptosis. Thus, PIAS1 determines the level of JNK activity in HESCs, couples ROS signaling to the SUMO pathway, and promotes oxidative cell death.-Leitao, B. B., Jones, M. C., Brosens, J. J. The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death.

Item Type: Journal Article
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016)
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Journal or Publication Title: FASEB Journal
Publisher: Federation of American Societies for Experimental Biology
ISSN: 0892-6638
Official Date: October 2011
Dates:
DateEvent
October 2011Published
Volume: Vol.25
Number: No.10
Page Range: pp. 3416-3425
DOI: 10.1096/fj.11-186346
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: Wellcome Trust (WT), Genesis Trust , UK National Institute for Health Research Biomedical Research Centre
Grant number: 084336 (WT)

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