Temporal Coordination of the Transcription Factor Response to H 2 O 2 stress.

The p53 and FOXO transcription factors (TFs) share many similarities despite their distinct evolutionary origins. Both TFs are activated by a variety of cellular stresses and upregulate genes in similar pathways including cell-cycle arrest and apoptosis. Oxidative stress from excess H 2 O 2 activates both FOXO1 and p53, yet whether they are activated at the same time is unclear. Here we found that cells respond to high H 2 O 2 levels in two temporal phases. In the first phase FOXO1 rapidly shuttles to the nucleus while p53 levels remain low. In the second phase FOXO1 exits the nucleus and p53 levels rise. We found that other oxidative stress induced TFs are activated in the first phase with FOXO1 (NF-kB, NFAT1), or the second phase with p53 (NRF2, JUN) but not both following H2O2 stress. The two TF phases result in large differences in gene expression patterns. Finally, we provide evidence that 2-Cys peroxiredoxins control the timing of the TF phases in response to H 2 O 2 .