Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate
Autor: | Andrea Gille, Abdullah Turkistani, Dimitrios Tsitsipatis, Xiaoqing Hou, Sarah Tauber, Ingrit Hamann, Nadine Urban, Katrin Erler, Holger Steinbrenner, Lars-Oliver Klotz |
---|---|
Rok vydání: | 2018 |
Předmět: |
Cell Nucleus
endocrine system lcsh:R5-920 Forkhead Box Protein O1 NF-E2-Related Factor 2 Recombinant Fusion Proteins Intracellular Space Maleates Hep G2 Cells digestive system Glutathione Models Biological Protein Transport HEK293 Cells lcsh:Biology (General) Stress Physiological Animals Humans Phosphorylation lcsh:Medicine (General) Caenorhabditis elegans lcsh:QH301-705.5 hormones hormone substitutes and hormone antagonists |
Zdroj: | Redox Biology, Vol 20, Iss, Pp 19-27 (2019) |
ISSN: | 2213-2317 |
Popis: | Diethyl maleate (DEM), a thiol-reactive α,β-unsaturated carbonyl compound, depletes glutathione (GSH) in exposed cells and was previously shown by us to elicit a stress response in Caenorhabditis elegans that, at lower concentrations, results in enhanced stress resistance and longer lifespan. This hormetic response was mediated through both the Nrf2 ortholog, SKN-1, and the forkhead box O (FOXO) family transcription factor DAF-16. As FOXO signaling is evolutionarily conserved, we analyzed here the effects of DEM exposure on FOXO in cultured human cells (HepG2, HEK293). DEM elicited nuclear accumulation of GFP-coupled wild-type human FOXO1, as well as of a cysteine-deficient FOXO1 mutant. Despite the nuclear accumulation of FOXO1, neither FOXO1 DNA binding nor FOXO target gene expression were stimulated, suggesting that DEM causes nuclear accumulation but not activation of FOXO1. FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM, suggesting that DEM interfered with nuclear export. In addition, insulin-induced FOXO1 phosphorylation at Thr-24, which is associated with FOXO1 nuclear exclusion, was attenuated upon exposure to DEM. Different from FOXO-dependent expression of genes, Nrf2 target gene mRNAs were elevated upon exposure to DEM. These data suggest that, different from C. elegans, DEM elicits opposing effects on the two stress-responsive transcription factors, Nrf2 and FOXO1, in cultured human cells. Keywords: FOXO, DAF-16, Glutathione, Stress response, Nrf-2, Thiols, Nuclear export |
Databáze: | OpenAIRE |
Externí odkaz: |