Temporal coordination of the transcription factor response to H 2 O 2 stress.

Oxidative stress from excess H 2 O 2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H 2 O 2 , it is unclear whether they are activated at the same H 2 O 2 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 H 2 O 2 activate p53, NRF2 and JUN. Yet under high H 2 O 2 , 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 H 2 O 2 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.