Review
Cell cycle and death control: long live Forkheads

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Abstract

The FOXO family of Forkhead transcription factors, FKHR (FOXO1), FKHR-L1 (FOXO3a) and AFX (FOXO4), are regulated by the phosphoinositide-3-kinase–protein-kinase-B (PI3K–PKB/c-Akt) pathway. Direct phosphorylation by PKB results in cytoplasmic retention and inactivation, inhibiting the expression of FOXO-regulated genes, which control the cell cycle, cell death, cell metabolism and oxidative stress. This pathway appears to be well conserved throughout evolution. In the nematode Caenorhabditis elegans, it affects lifespan and controls dauer formation. Recent discoveries about FOXO regulation by PI3K–PKB signalling suggest that the PI3K–PKB–FOXO pathway might participate in similar processes in higher eukaryotes.

Section snippets

Brief description of a signalling pathway

Binding of ligands to their cognate receptor initiates intracellular signalling through the recruitment and activation of proteins withs various enzymatic activities (Fig. 1). Insulin binding to the insulin receptor activates several distinct signalling molecules and, of these, PI3K appears to be crucial for insulin's ability to regulate metabolic homeostasis and protection from cell death [1]. Molecular analysis of PI3K revealed it to be a heterodimer consisting of a regulatory p85 and a

Regulation of FOXO activity by PKB

Forkhead factors are classified based on their conserved DNA-binding domain, which is characterized by three α-helices and two characteristic large loops, or ‘wings’. Recently a new nomenclature for these factors has been adopted and Forkhead factors are now denoted FOX (Forkhead box) factors [11]. Within the larger family of FOX factors, the proteins AFX, FKHR and FKHR-L1 constitute the FOXO group; FKHR is now known as FOXO1, FKHR-L1 as FOXO3a and AFX as FOXO4. FOX factors bind DNA as a

Phosphorylation by alternative signalling pathways

Transcription factors are often the convergence point of multiple signalling pathways. As indicated in Fig. 3, not all phosphorylation of FOXO members occurs as a result of PI3K–PKB signalling. For example, it was reported that serum- and glucocorticoid-inducible kinase (SGK) can also phosphorylate T1 and S2 of FOXO3a [25]. Like PKB, SGK is a member of the AGC-kinase family and PDK1 appears to be responsible for T-loop phosphorylation and activation of SGK, just as it phosphorylates PKB [26].

Gene regulation and cellular responses in mammalian cells

Studies in mammalian cells have shown that the overproduction of FOXO4, FOXO1 and FOXO3a induces either cell cycle arrest or apoptosis (Fig. 4). By increasing the production of the cyclin-dependent-kinase inhibitor p27kip1, these FOXO factors cause cell cycle arrest in the G1 phase of the cell cycle [29]. Regulation of p27kip1 levels was thought to occur predominantly at the post-transcriptional level, through the regulation of ubiquitin-mediated degradation. However, FOXO members were shown to

FOXO members and cellular transformation

A role for FOXO members in cell transformation and tumorigenesis was initially suggested by the observation that FOXO members are part of chromosomal translocations in certain types of tumour [42]. In these tumours, the fusion protein resulting from these translocations might contribute to tumorigenesis, because the fusion protein can transform cells in culture [43]. However, these translocations might also result in partial FOXO-protein inactivation owing to the loss of a FOXO allele.

A role

From human to worm and back: what's the future for FOXO members?

Although the picture is still far from complete, the PI3K–PKB–FOXO pathway appears to be remarkably conserved during evolution, at least at the structural level. In C. elegans, signalling by an insulin-type receptor (DAF-2) negatively regulates the activity of a Forkhead transcription factor, DAF-16 44., 45.. By genetic means, components that mediate signalling from DAF-2 to DAF-16 have been identified, and it was shown that DAF-16 regulation requires a PI3K type of protein (AGE-1) as well as

Acknowledgements

We thank K. Reedquist, F. Zwartkruis, R. Medema and H. Bos for critically reading the article, and all members of our laboratory for continuous discussion. Our work cited here was financially supported by the Dutch Cancer Foundation (KWF) and the Dutch Organization for Scientific Research (NWO).

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      We interrogated an intracellular signaling pathway frequently hyperactivated in human cancers and mediated by the enzymes phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) (Fresno Vara et al., 2004; Vivanco and Sawyers, 2002). Its constitutive activation inactivates the tumor-suppressive transcription factor, FOXO3a (Brunet et al., 1999; Burgering and Kops, 2002), by inducing its phosphorylation and cytosolic sequestration by factors such as the 14-3-3 protein family (Brunet et al., 2002; Mackintosh, 2004; Van Der Heide et al., 2004). Cytosolic FOXO3a sequestration and inactivation has been implicated in tumorigenesis (Dansen and Burgering, 2008; Hu et al., 2004; Liu et al., 2018; Yang et al., 2008) and signifies poor prognosis in a wide range of human tumors (Ni et al., 2014; Santo et al., 2013; Xie et al., 2012; Yang et al., 2013).

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