@article{8f731ab5e4bb4ca5b73928c6abb913a0,
title = "Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis",
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.",
keywords = "Endoderm development, Liver cancer, Selenium, Selenoproteins, p53",
author = "Cox, {Andrew G.} and Allison Tsomides and Kim, {Andrew J.} and Diane Saunders and Hwang, {Katie L.} and Evason, {Kimberley J.} and Jerry Heidel and Brown, {Kristin K.} and Min Yuan and Lien, {Evan C.} and Lee, {Byung Cheon} and Sahar Nissim and Bryan Dickinson and Sagar Chhangawala and Chang, {Christopher J.} and Asara, {John M.} and Yariv Houvras and Gladyshev, {Vadim N.} and Wolfram Goessling",
note = "Funding Information: This work was supported by an Irwin Arias Postdoctoral Fellowship (to A.G.C.) and Liver Scholar Award (to A.G.C.) from the American Liver Foundation; Harvard Digestive Disease Center Pilot Feasibility Grant P30 DK034854 (to A.G.C.); and National Institutes of Health (NIH) Grants T32GM007753 (to K.L.H.), NCI 5K08CA172288 (to K.J.E.), R01 GM061603 (to V.N.G.), and R01 DK090311 and R24OD017870 (to W.G.). K.J.E. was a Robert Black Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-109-10). C.J.C. is an Investigator with the Howard Hughes Medical Institute and has received support from NIH Grant GM 79465. J.M.A. is partially supported by NIH Grants 5P01CA120964 and 5P30CA006516. W.G. is supported by the Claudia Adams Barr Program for Innovative Cancer Research and is a Pew Scholar in the Biomedical Sciences. Publisher Copyright: {\textcopyright} 2016, National Academy of Sciences. All rights reserved.",
year = "2016",
month = sep,
day = "20",
doi = "10.1073/pnas.1600204113",
language = "English",
volume = "113",
pages = "E5562--E5571",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "38",
}
