Abstract
Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a variety of stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. FOXO3a activity is regulated by post-translational modifications that drive its shuttling between different cellular compartments, thereby determining its inactivation (cytoplasm) or activation (nucleus and mitochondria). Depending on the stress stimulus and subcellular context, activated FOXO3a can induce specific sets of nuclear genes, including cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species (ROS) scavengers, autophagy effectors, gluconeogenic enzymes, and others. On the other hand, upon glucose restriction, 5′-AMP-activated protein kinase (AMPK) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -dependent FOXO3a mitochondrial translocation allows the transcription of oxidative phosphorylation (OXPHOS) genes, restoring cellular ATP levels, while in cancer cells, mitochondrial FOXO3a mediates survival upon genotoxic stress induced by chemotherapy. Interestingly, these target genes and their related pathways are diverse and sometimes antagonistic, suggesting that FOXO3a is an adaptable player in the dynamic homeostasis of normal and stressed cells. In this review, we describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions.
Highlights
During the evolution of prokaryotic and eukaryotic organisms, cells have developed an extraordinary capacity to adapt to adverse changes in their environment.Organisms and their cells are exposed to a broad spectrum of harmful events arising from physiological processes and/or external stimuli
These processes involve: i) The metabolic/energetic response system, which is induced by fluctuations in metabolites, including nutrients [3]; ii) the oxidative stress response system, which is activated by excess reactive oxygen species (ROS) and imbalances in the oxidant/antioxidant status within cells [4,5]; iii) the hypoxia response system, which becomes operational in low oxygen conditions [6]; iv) the heat shock response system, which is elicited by exposure to heat and other agents that adversely affect protein folding and impair RNA metabolism [7]; and v) the genotoxic response system, which is triggered by DNA damage [8]
Several findings suggest that FOXO3a is a crucial target of hypoxia-inducible factor (HIF)-mediated sensing of cellular stress, since hypoxia can directly induce FOXO3a expression and nuclear localization, and these processes are associated with HIF activation [76,77]
Summary
Candida Fasano 1,† , Vittoria Disciglio 1,† , Stefania Bertora 1,† , Martina Lepore Signorile 1,2 and Cristiano Simone 1,3, *. Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy. Received: 31 August 2019; Accepted: September 2019; Published: September 2019
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