OP-06 - Redox regulation of FOXO transcription factors – role of glutathione

Abstract

FOXO transcription factors are involved in the cellular adaptive response to oxidative stimuli. FOXO activity is affected by the modulation of thiol levels both in cultured mammalian cells and in the model organism Caenorhabditis elegans. Exposure of HepG2 cells to diethyl maleate (DEM) resulted in a nuclear accumulation of overexpressed FOXO1-GFP. Pre- or postincubation of cells with DEM prevented or reversed this effect, triggering nuclear accumulation of FOXO-GFP. Similarly, the FOXO ortholog in C. elegans, DAF-16, accumulated in nuclei upon exposure of worms to DEM. DAF-16 was also essential to DEM-induced life span extension. Moreover, the expression of cytoprotective DAF-16 target genes was increased in worms held on DEM. These beneficial effects were observed only at low concentrations of DEM (10-100 µM), whereas higher concentrations (1 mM) were detrimental. Downregulation of GSH levels in young adult worms through attenuation of gcs-1 expression increased both stress resistance and life expectancy of the worms. In contrast, gcs-1 knockdown right after hatching rendered young adult worms susceptible to vulval ruptures during egg-laying. Thus, modest GSH depletion in young adult worms may promote stress resistance and life span, whereas depletion of GSH may be detrimental to developing worms.