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FOXOs: signalling integrators for homeostasis maintenance

Key Points

  • The forkhead box O (FOXO) family of transcription factors consists of four members: FOXO1, FOXO3, FOXO4 and FOXO6. At the cellular level, FOXO transcriptional targets are involved in the regulation of cell cycle, apoptosis, oxidative stress resistance and metabolism.

  • FOXOs integrate signals from multiple upstream pathways and are activated by metabolic and oxidative stress and by the absence of growth factors. This regulation of FOXO activity is accomplished through various post-translational modifications, nuclear–cytoplasmic localization of FOXOs and their regulators, specific microRNAs (miRNAs) and interactions with other transcription factors.

  • The biological role of FOXOs is predominately to respond to stress conditions rather then being an essential mediator of normal physiology. Generally, by responding to and counteracting environmental changes, FOXOs act to maintain homeostasis.

  • In model organisms, FOXO function is diverse and mostly comes into focus under conditions that disturb homeostasis. Conditional knockout models have revealed functions in tumour suppression, metabolic stress and protein homeostasis, stem cell maintenance as well as specific roles in the immune system.

  • The role of FOXOs in maintaining cellular homeostasis reveals many similarities with the role of p53 in maintaining genome homeostasis, and these factors share co-regulators.

  • FOXOs were initially characterized as tumour suppressors. However, FOXOs have also been shown to act as tumour promoters. This seemingly paradoxical outcome of being both tumour suppressor and tumour promoter can be reconciled by postulating that FOXOs act as homeostasis regulators of both normal and cancer cells.

Abstract

Forkhead box O (FOXO) transcription factors are involved in the regulation of the cell cycle, apoptosis and metabolism. In model organisms, FOXO activity also affects stem cell maintenance and lifespan as well as age-related diseases, such as cancer and diabetes. Multiple upstream pathways regulate FOXO activity through post-translational modifications and nuclear–cytoplasmic shuttling of both FOXO and its regulators. The diversity of this upstream regulation and the downstream effects of FOXOs suggest that they function as homeostasis regulators to maintain tissue homeostasis over time and coordinate a response to environmental changes, including growth factor deprivation, metabolic stress (starvation) and oxidative stress.

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Figure 1: Control of FOXO and outcomes of FOXO activation.
Figure 2: Regulation of FOXO activity by controlled subcellular localization of FOXO and its regulators.
Figure 3: FOXOs participate in various forms of crosstalk.
Figure 4: FOXOs as homeostasis regulators.

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Acknowledgements

The authors thank G. Kops and R. Martinez for critical reading of the manuscript and discussion. Research in the Burgering laboratory is funded by the Dutch Cancer Society (KWF), the Netherlands Organisation for Scientific Research (NWO) and the Centre of Biomedical Genetics (CBG). A.E. is supported by the Centre of Translational Molecular Medicine (CTMM) Research.

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Glossary

Homeostasis

The ability of an organism, or its constituent cells and organs, to establish and maintain an equilibrium that stabilizes its internal milieu and optimizes its ability to deal with moderate external changes.

Dauer stage

An alternative developmental stage of nematode worms, including Caenorhabditis elegans, in which larva are adapted so that they can survive harsh conditions for an extended period of time.

CBP–p300

A co-activator family composed of two closely related transcriptional co-activators. They regulate transcription by relaxing chromatin structures through histone acetylation, by recruiting the basal transcription machinery, including RNA polymerase II, and by acting as adaptor molecules.

Methylation

The addition of a methyl group to a substrate. Protein methylation typically takes place on Arg or Lys residues, adding a maximum of two or three methyl groups, respectively.

O-linked-D-N-acetylglucosamine

(O-GlcNAc). A monosaccharide derivative of glucose that is added as a post-translational modification on Ser and Thr residues.

Cys oxidation

The thiol group of Cys residues can be easily oxidized, which can result in the formation of disulphide bonds with a Cys residue in the same or another protein.

Epigenetic code

Hypothesized to be a defining code in every eukaryotic cell that consists of specific epigenetic modifications. It includes histone modifications defined by the histone code and additional epigenetic modifications such as DNA methylation.

microRNAs

(miRNAs). Short RNAs found in eukaryotic cells that can post-transcriptionally regulate gene expression through binding to complementary sequences in target mRNAs. This usually results in translational repression or target degradation.

Haploinsufficient

Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene, and the single functional copy of the gene does not produce enough of a gene product, which leads to an abnormal or diseased state.

T cells

Lymphocytes that are essential components of the adaptive immune system and are mainly involved in cell-mediated immunity.

PML bodies

(Promyelocytic leukaemia bodies). Spherical bodies that are found scattered throughout the nucleoplasm. PML bodies have been suggested to affect transcription regulation.

Nucleolus

A non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. The nucleolus is the location of rRNA transcription and assembly but can also capture and immobilize proteins.

Pioneer factors

Although the precise definition is still debated, pioneer factors are thought to be transcription factors that can initially bind regulatory sequences, allowing binding of other factors by opening compacted chromatin, ultimately enabling transcriptional activation.

Metabolic syndrome

A combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes.

AGRP-neurons

(Agouti-related protein (AGRP)-expressing neurons). Hypothalamic neurons that express AGRP regulate food intake by stimulating feeding and inhibiting satiety.

Autophagy

A tightly regulated catabolic process (also known as autophagocytosis) that involves the degradation of cellular components through the lysosomal machinery.

Mitophagy

An autophagy pathway that selectively degrades mitochondria.

Pluripotency

Pluripotency refers to a state of a cell, which has the potential to differentiate into any of the three germ layers (endoderm, mesoderm and ectoderm) and can give rise to any fetal or adult cell type.

B cell

A lymphocyte and essential component of the adaptive immune system. The principal functions of B cells are to generate antibodies against antigens, act as antigen-presenting cells and eventually develop into memory B cells.

Regulatory T cells

A subset of T cells that are also known as suppressor T cells. Their major role is to shut down T cell-mediated immunity towards the end of an immune reaction.

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Eijkelenboom, A., Burgering, B. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14, 83–97 (2013). https://doi.org/10.1038/nrm3507

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