Stressing the role of FoxO proteins in lifespan and disease

  title={Stressing the role of FoxO proteins in lifespan and disease},
  author={Armando van der Horst and Boudewijn M. T. Burgering},
  journal={Nature Reviews Molecular Cell Biology},
Members of the class O of forkhead box transcription factors (FoxO) have important roles in metabolism, cellular proliferation, stress tolerance and probably lifespan. The activity of FoxOs is tightly regulated by post-translational modifications, including phosphorylation, acetylation and ubiquitylation. Several of the enzymes that regulate the turnover of these post-translational modifications are shared between FoxO and p53. These regulatory enzymes affect FoxO and p53 function in an… 

FoxO transcription factors in oxidative stress response and ageing – a new fork on the way to longevity?

A brief review focuses on the molecular mechanisms, cellular effects and resulting organismal phenotypes generated by differentially regulated FoxO proteins and discusses the current understanding of the role of FoxOs in disease and ageing processes.

Post-translational regulation of FOXO.

The Forkhead box O (FOXO) family transcription factors play critical roles in a series of cellular processes, including the cell cycle, cell death, metabolism, and oxidative stress resistance. FOXO

FOXOs: signalling integrators for homeostasis maintenance

Multiple upstream pathways regulate FOXO activity through post-translational modifications and nuclear–cytoplasmic shuttling of both FOXO and its regulators, suggesting that they function as homeostasis regulators to maintain tissueHomeostasis over time and coordinate a response to environmental changes.

Structure/function relationships underlying regulation of FOXO transcription factors

This review focuses on recent advances in structural studies of forkhead transcription factors and the insights they provide into the mechanism of DNA recognition and the nuclear localization signal of FOXO proteins.

Many forks in the path: cycling with FoxO

A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of thecell cycle.

Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase.

Nemo-like kinase (NLK) is described as a novel regulator of FOXOs and shown that NLK-mediated loss of FOXO4 activity co-occurs with inhibition ofFOXO4 monoubiquitination, which leads to activation of an antioxidant defensive program.

Forkhead box(O) in control of reactive oxygen species and genomic stability to ensure healthy lifespan.

Possible connections between FOXO and the DNA damage response in the context of the broader role of connecting lifespan and disease are discussed.

Forkhead box class O transcription factors in liver function and disease

This review summarizes emerging knowledge of FOXO function in the liver, FOXO changes in liver disease, and the posttranslational modifications responsible for these effects.

The roles of FoxOs in modulation of aging by calorie restriction

Increased modification of FoxO is modulated via the hyperinsulinemia-induced PI3K/Akt pathway during aging, and CR reverses this process, and FoxO plays an important role in maintenance of metabolic homeostasis and removal of oxidative stress in the aging process and in the effect of CR on lifespan.

Forkhead Domains of FOXO Transcription Factors Differ in both Overall Conformation and Dynamics

The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility, which will support the development ofFOXO-type-specific inhibitors.



Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

One way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

The interaction between FOXO and SIRT1: tipping the balance towards survival.

FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP

It is shown that FOXO becomes monoubiquitinated in response to increased cellular oxidative stress, resulting in its re-localization to the nucleus and an increase in its transcriptional activity.

SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress.

It is demonstrated that mammalian SIRT1 (Sir2alpha) physiologically interacts with FOXO and plays a pivotal role for FOXO function via NAD-dependent deacetylation in response to oxidative stress, and thereby may contribute to cellular stress resistance and longevity.

FOXO transcription factors at the interface between longevity and tumor suppression

Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity and suggests that FOXO factors play a tumor suppressor role in a variety of cancers.

Cell cycle and death control: long live Forkheads.

Mammalian SIRT1 Represses Forkhead Transcription Factors

FOXO4 Is Acetylated upon Peroxide Stress and Deacetylated by the Longevity Protein hSir2SIRT1*

It is demonstrated that acetylation functions in a second pathway of negative control for FOXO factors and provides a novel mechanism whereby hSir2SIRT1 can promote cellular survival and increase lifespan.

Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway

In mammalian cells, p53, Foxo3a, and SIRT1, three proteins separately implicated in aging, constitute a nutrient-sensing pathway.

Functional Interaction Between ß-Catenin and FOXO in Oxidative Stress Signaling

An evolutionarily conserved interaction of β-catenin with FOXO transcription factors, which are regulated by insulin and oxidative stress signaling, is reported, demonstrating a role for β-Catenin in regulating FOXO function that is particularly important under conditions of oxidative stress.