Yang, Y, Yu, S, Liu, N et al. (9 more authors) (2018) Transcription Factor FOXO3a Is a Negative Regulator of Cytotoxicity of Fusarium mycotoxin in GES-1 Cells. Toxicological Sciences, 166 (2). pp. 370-381. ISSN 1096-6080
Abstract
Molecular mechanism and key factors responsible for cytotoxicity against mycotoxin deoxynivalenol (DON) from Fusarium pathogens are rarely elucidated. In this study, rapid increases of ROS were first observed in human gastric epithelial (GES-1) cells under DON exposure. Mitochondrial DNA damage, impaired respiratory chain, and decreased oxygen consumption rate (OCR) values, as well as G2/M cell cycle arrest and apoptosis, were also detected. Via combinatorial approaches of a large-scale microarray of differentially expressed genes, high content and RNAi analysis, a transcription factor of Forkhead box O3 (FOXO3a) was found with crucial functionalities, regulated some apoptotic genes associated with mitochondrial toxicity and cell death after activation by nuclear translocation. Namely, knockdown of FOXO3a decreased the cytotoxicity of DON to GES-1 cells. Moreover, knockdown of the FOXO ortholog DAF16 in Caenorhabditis elegans increased the resistance to DON-induced cytotoxicity. Simultaneously, the signaling pathway of ROS/JNK/FOXO3a of DON-induced cytotoxicity was newly proposed. In total, FOXO3a via ROS/JNK/FOXO3a plays a critical role to function as negative regulator associating with DON-induced cytotoxicity, with the potential extending to other substances.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Keywords: | DAF16; FOXO3a nuclear translocation; mitochondrial dysfunction; oxidative stress; ROS/JNK/FOXO3a |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Environment (Leeds) > School of Food Science and Nutrition (Leeds) > FSN Chemistry and Biochemistry (Leeds) |
Funding Information: | Funder Grant number Bill & Melinda Gates Foundation EBSG/SSB/PS/VOL VII/099 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Nov 2021 15:25 |
Last Modified: | 30 Nov 2021 15:25 |
Status: | Published |
Publisher: | Oxford University Press |
Identification Number: | 10.1093/toxsci/kfy216 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:181021 |