Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis
Name
Cox-2016-Selenoprotein H is a.pdf
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Author(s)
Cox, Andrew G.
Tsomides, Allison
Kim, Andrew J.
Saunders, Diane
Hwang, Katie L.
Evason, Kimberley J.
Heidel, Jerry
Brown, Kristin K.
Yuan, Min
Lien, Evan C.
Date Issued
September 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Cox, Andrew G. et al. “Selenoprotein H Is an Essential Regulator of Redox Homeostasis That Cooperates with p53 in Development and Tumorigenesis.” Proceedings of the National Academy of Sciences 113.38 (2016): E5562–E5571. © 2017 National Academy of Sciences
Version
Final published version
Abstract
Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1600204113
