A Cooperative Role for Atf1 and Pap1 in the Detoxification of the Oxidative Stress Induced by Glucose Deprivation in Schizosaccharomyces pombe

Abstract

In Schizosaccharomyces pombe, glucose concentrations below a certain threshold trigger the stress-activated protein kinase (SAPK) signal transduction pathway and promote increased transcription of Atf1-dependent genes coding for the general stress response. Removal of glucose specifically induces the nuclear accumulation of green fluorescent protein-labeled Pap1 (GFP-Pap1) and the expression of genes dependent on this transcription factor. In contrast, depletion of the nitrogen source triggers the SAPK pathway but does not activate Pap1-dependent gene transcription, indicating that carbon stress rather than growth arrest leads to an endogenous oxidative condition that favors nuclear accumulation of Pap1. The reductant agents glutathione or N-acetylcysteine suppress the nuclear accumulation of GFP-Pap1 induced by glucose deprivation without inhibiting the activation of the MAPK Sty1. In addition, cells expressing a mutant GFP-Pap1 unable to accumulate into the nucleus upon hydrogen peroxide-mediated oxidative stress failed to show this protein into the nucleus in the absence of glucose. These results support the concept of a concerted action between the SAPK pathway and the Pap1 transcription factor during glucose exhaustion by which glucose limitation induces activation of the SAPK pathway prior to the oxidative stress caused by glucose deprivation. The ensuing induction of Atf1-dependent genes (catalase) decreases the level of hydroperoxides allowing Pap1 nuclear accumulation and function. Congruent with this interpretation, glucose-depleted cells show higher adaptive response to exogenous oxidative stress than those maintained in the presence of glucose.

Effects of glucose sensing/signaling on oxidative stress response in glucose repression mutants of Schizosaccharomyces pombe

“…Therefore, the elevated expression of the fbp1 gene in ird mutants (Figure 2) might be because of a lack of glucose repression. In addition, the high resistance of ird mutants to oxidative stress might result from a lack of glucose repression because it is known that glucose depletion causes resistance to oxidative stress in S. pombe (Madrid et al, 2004;Roux et al, 2009). …”

“…Atf1 and Pap1 are known to be involved in the regulation of the cellular defense mechanism(s) against increasing oxidative stress in aerobically growing, glucose-depleted cells (Madrid et al, 2004). These transcription factors have been proposed to be activated under mild oxidative stress conditions in S. pombe (Quinn et al, 2002).…”

“…On the other hand, the high resistance to oxidative stress under glucose depletion either involves the induction of a wide array of stress-responsive genes due to carbon stress (Madrid et al, 2004) or is a defense mechanism against the increased accumulation of reactive oxygen species that are derived from aerobic respiration (Roux et al, 2009). Lin et al (2002) reported that an S. cerevisiae strain with a deletion of the HXK2 gene, which is involved in glycolysis, mimics the effect of growth in low glucose and extends the life span.…”

A potential protective role for thiamine in glucose-driven oxidative stress

“…We compared the expression level of the sty1 gene encoding MAPK Sty1p, which increases the expression of various stress-responsive genes through the activation of the Atf1p and Pap1p transcription factors in S. pombe (Madrid et al, 2004), both in ird11 and wild type cells. In this study, no significant increase was observed in sty1 expression in ird11 under the nonstressed condition, whereas the expression level of sty1 decreased in ird11 under the stressed condition.…”

“…Furthermore, the activity of Ght3 is optimal at low glucose concentration (0.2%), 2% D-gluconate, or 2% maltose. Recently, it was reported that glucose depletion or respiratory growth on nonfermentable carbon sources leads to an increased oxidative stress response (Chen et al, 2003;Madrid et al, 2004;Kim et al, 2006;Chen and Runge, 2009) and extends life span in S. pombe (Lin et al, 2002;Roux et al, 2009Roux et al, , 2010.…”