FOXO4 is a ubiquitously expressed protein member of a subfamily of the forkhead homeotic gene family of transcription factors and shuttles between the cytoplasm and nucleus. FOXO transcription factors are key players of cell fate decisions, metabolism, stress resistance, tumor suppression and are regulated by growth factors, oxidative stress or nutrient deprivation. In the absence of PI3K/AKT activation, FOXO4 localizes in the nucleus where it functions as a transcription factor. FOXO4 can also be phosphorylated by JNK following induction of reactive oxygen species (ROS), resulting in transcriptional activation and the induction of a negative feedback mechanism to counteract the ROS. It is through this mechanism that FOXO4 is thought to sensitize cancer cells to doxorubicin-mediated toxicity.

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