Stress-Induced Dynamics of FOXO Transcription Factors

Abstract

The FOXO family of transcription factors have several important roles in multicellular organisms: they are required for proper development of different tissues, maintain homeostasis in response to diverse cellular stresses, function as tumor suppressors, and have an evolutionarily conserved role in prolonging lifespan. Consistent with their role in diverse cellular processes, FOXO proteins are activated by several different stimuli, leading to the promotion of many different downstream programs often with opposing outcomes. How FOXO protein activation can lead to stimulus-dependent transcriptional outcomes is not known, though several mechanisms have been proposed. Possible mechanisms include differences in FOXO post-translational modifications, binding partners, and the dynamics of FOXO activation. Here, I will describe the current evidence in the literature supporting these mechanisms, and our investigation into the role of dynamic patterns of activation of the FOXO transcription factors. Specifically, I set out to determine whether FOXO responds to different stresses with different temporal patterns of activation. I have shown that FOXO responds to oxidative stress in a sustained, bimodal pattern, while it responds to serum starvation in a stochastic pulsatile pattern. I also found that in MCF7 breast cancer cells, both patterns are controlled by the activity of the primary negative regulator of FOXO, Akt.