FOXO4 (also known as AFX) is a member of the Forkhead familiy of transcription factors ^[1] and forms a subclass with FOXO1 (FKHR), FOXO3A (FKHRL1) and FOXO6. The FOXO transcription factors are key players in regulation of cell-fate decisions (cell death, cell proliferation and cell metabolism, see FIGURE 1) and are considered to be tumor suppressors ^[2]. In model organisms FOXO was shown to increase longevity^[3] and this function was shown to be dependent on FOXO's ability to induce oxidative stress inducing genes^[4]. The FOXO subclass members 1, 3a and 4 are ubiquitously expressed, but their respective levels differ per cell type or organ ^[5], whereas FOXO6 expression seems to be restricted to the brain.

All FOXOs consist of a forkhead DNA binding domain, nuclear localization signal (NLS), nuclear export sequence (NES) and transactivation domain (TA). The DNA binding domain is highly conserved within the FOXO family and is shown to bind the core consensus DNA sequence 5` TTGTTTAC 3`^[5]. Overlap in target genes is thus expected and has been shown. Indeed studies in FOXO1, FOXO3a and FOXO4 knockout mice show that FOXO tumor suppressive function is intact in mice lacking any combination of two, but not all three, FOXO genes^[6]. Any functional specificity in function is likely to be obtained through posttranslational modifications and interaction with specific co-factors.

The activity of FOXO family members FOXO1, FOXO3 and FOXO4 is regulated by cellular localization and several posttranslational modifications like phosphorylation, acetylation and ubiquitination (see FIGURE 2). Some of these modifications induce a change in subcellular localization of FOXO. For instance, FOXO activity is negatively regulated by PI3-K via PKB/Akt in response to insulin through phosphorylation, resulting in translocation of the transcription factors from nucleus to cytoplasm ^{[7][8][9] [10]}, whereas stress induced kinases like JNK positively regulate FOXO nuclear localization and transcriptional activity ^[11][12][13](see FIGURE 3 for a model of the regulation of FOXO transcriptional activity by posttranslational modifications).

For more information and reviews, we would like to refer to an issue of Oncogene Reviews, completely dedicated to the FOXO family of forkhead transcription factors (volume 27, number 16 – April 7, 2008).