Temporal Coordination of the Transcription Factor Response to Hydrogen Peroxide Stress

Abstract

The non-radical reactive oxygen species, hydrogen peroxide (H2O2), plays a multifaceted role within the cell. At low concentrations it acts as a signaling molecule promoting cell growth, survival and adaptation to stress. However, at high concentrations it becomes toxic inducing cell death. To enact distinct cell outcomes based on the concentration of H2O2, cells possess sensor proteins by which they can gauge the levels of peroxide present. One well known sensor of H2O2 levels are the thiol proteins, peroxiredoxins. These proteins not only detoxify the excess peroxide but can also relay the signal from H2O2 to proteins like transcription factors (TF). Activation of different sets of TFs depending on the levels of peroxide help the cell coordinate gene expression which ultimately determines cell fate. Here we describe a well-coordinated system through which cells can sense and regulate their response to H2O2 based on its concentration.In this dissertation, we found that the TF response to H2O2 occurs in two distinct temporal phases. We specifically looked at two TFs, FOXO and p53, both activated by H2O2. In response to low levels of H2O2, cells activate p53, while FOXO remains inactive. However, at higher concentrations of H2O2, cells respond in two phases: Phase 1, where FOXO is activated, followed by Phase2, where FOXO1 is switched off and p53 is activated. We found that the duration of Phase 1 increases with concentration of H2O2. Interestingly we find that other TFs activated by H2O2 also fall into these two phases, with NF-kB and NFAT activated with FOXOs in phase 1 and NRF2 and JUN activated later with p53. The two different TF phases result in very different gene expression patterns. Finally, we show that the timing of activation of each phase is controlled by the peroxiredoxin system.