Temporal Coordination of the Transcription Factor Response to H₂O₂stress

Abstract

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 H2O2activates both FOXO1 and p53, yet whether they are activated at the same time is unclear. Here we found that cells respond to high H2O2levels 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-κB, NFAT1), or the second phase with p53 (NRF2, JUN) but not both following H2O2stress. 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 H2O2.

Oxidative stress controls lncRNA-mediated granulosa cell functions in a FoxO1-dependent manner

“…FoxO1 is a component of the Forkhead box O (FOXO) family of TFs that are known to respond to many biological stressors, including OS, which plays a crucial role in both physiological and disease processes [22][23][24]. On the one hand, FoxO1 serves as an effector in response to OS, with the rise in OS-stimulated cells such as sGCs [7], MCF7 cells [25], and KGN cells [26]. On the other hand, FoxO1 also acts as a TF to transmit OS signals to the nucleus, activate or inhibit the transcription of downstream genes, and mediate OS's regulation of cellular functions [27,28].…”

MLIP and Its Potential Influence on Key Oncogenic Pathways

“…However, p53 and forkhead box O family (FOXO), downstream of the PI3K/Akt/mTOR pathway, respectively, are critical integrators of genomic and metabolic stresses [5][6][7][8]. Both p53 and FOXO are stress-activated transcription factors that promote an adaptive pro-survival response to insult [9][10][11]. Specifically, p53 stimulates DNA repair in response to DNA damage [12,13] and FOXO regulates metabolic remodeling to maintain metabolic homeostasis [14][15][16].…”