Temporal coordination of the transcription factor response to H2O2 stress

Abstract

Oxidative stress from excess H₂O₂ activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H₂O₂, it is unclear whether they are activated at the same H₂O₂ concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H₂O₂ activate p53, NRF2 and JUN. Yet under high H₂O₂, these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H₂O₂ is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.