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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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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).

  1. Borkhardt A et al. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene, 14(2):195-202. (PMID 9010221)
  2. Dansen TB and Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol., 18(9):421-9. (PMID 18715783)
  3. Ogg S et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature, 389(6654):994-9. (PMID 9353126)
  4. Honda Y and Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J., 13(11):1385-93. (PMID 10428762)
  5. Furuyama T et al. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J., 349(Pt 2):629-34. (PMID 10880363)
  6. Paik JH et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell, 128(2):309-23. (PMID 17254969)
  7. Brunet A et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96(6):857-68. (PMID 10102273)
  1. Kops GJ et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature, 398(6728):630-4. (PMID 10217147)
  2. Rena G et al. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J. Biol. Chem., 274(24):17179-83. (PMID 10358075)
  3. Nakae J et al. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem., 274(23):15982-5. (PMID 10347145)
  4. Essers MA et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J., 23(24):4802-12. (PMID 15538382)
  5. Oh SW et al. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. U.S.A., 102(12):4494-9. (PMID 15767565)
  6. Wang MC et al. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell, 121(1):115-25. (PMID 15820683)
FIGURE 1 Figure 1: Transcriptional outputs of FoxO activity
Increased class O forkhead box transcription factor (FoxO) activity participates in several cellular processes, most notably inhibition of the cell cycle, regulation of cell death, protection from cellular (oxidative) stress and regulation of cellular metabolism (gluconeogenesis and fatty-acid oxidation). FoxO-regulated genes that are linked to these processes are indicated. The outcome of FoxO function is likely to be determined in conjunction with other genetic determinants, for example, the function of the tumour-suppressor protein p53. MnSOD, manganese superoxide dismutase; PEPCK, phosphenolpyruvate carboxykinase; SCPx, sterol carrier protein-x.
This figure is from a publication. Please click here to view the publication's entry in Pubmed (PMID 17522590).