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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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There are up to six suggested splice variants for FOXO3, although the two annotated variants encode the same protein [1]. The functions of these FOXO3 isoforms have not been established. However, two N-terminal truncated FOXO4 proteins (90 and 101 amino acids long) produced by aberrant splicing have been identified in cancer cells, and these variants fail to induce cell death [2].

A pseudogene for FOXO3 has also been found in humans, such that the gene is often called FOXO3a (while the pseudogene is FOXO3b) [3].

  1. Thierry-Mieg D and Thierry-Mieg J. AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol., 7 Suppl 1:S12.1-14. (PMID 16925834)
  2. Lee EJ et al. Splice variants of the forkhead box protein AFX exhibit dominant negative activity and inhibit AFXalpha-mediated tumor cell apoptosis. PLoS ONE, 3(7):e2743. (PMID 18648506)
  1. Arden KC. Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp. Gerontol., 41(8):709-17. (PMID 16806782)
Covalent modifications

Several important covalent post-translational modifications have been recorded for FOXO3a. These include phosphorylation, ubiquitination, methylation, and acetylation.

Akt (PKB) phosphorylates FOXO3 at three sites, Thr32, Ser253 and Ser315 [1]. These modifications result in binding of 14-3-3 proteins, and nuclear export. SGK (serum glucocorticoid kinase; related to Akt) can also act on these sites [2], and IKKβ (inhibitor of NFκB kinase β) can phosphorylate Ser644 [3]. In the cytoplasm, the sequestered FOXO3 is polyubiquitinated and degraded via the proteasome, though the identity of the ubiquitin ligase is not yet known [4]. The MAP kinase Erk also inhibits FOXO3 by phosphorylation; it acts on Ser294, Ser344 and Ser425, resulting in polyubiquitination and proteasomal degradation via MDM2 [5].

Conversely, phosphorylation by MST at Ser207 increases FOXO3 activity [6]. JNK may also activate FOXO3a by phosphorylation, as it acts on the related FOXO4 at Thr447 and Thr451 [7]. It is thought that PP2A (protein phosphatase 2A) plays a role in removing phosphate groups on FOXO3a added by Akt [8][9]. Methylation by PRMT1 (protein arginine methyltransferase 1), known to act on FOXO1 in vivo and FOXO3a in vitro, may inhibit phosphorylation by Akt [10]. Acetylation by proteins such as p300 and PCAF is important for regulating FOXO3a activity [11], as is deacetylation by SIRTs [12].

  1. Calnan DR and Brunet A. The FoxO code. Oncogene, 27(16):2276-88. (PMID 18391970)
  2. Brunet A et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol., 21(3):952-65. (PMID 11154281)
  3. Hu MC et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell, 117(2):225-37. (PMID 15084260)
  4. Huang H and Tindall DJ. Dynamic FoxO transcription factors. J. Cell. Sci., 120(Pt 15):2479-87. (PMID 17646672)
  5. Yang JY et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat. Cell Biol., 10(2):138-48. (PMID 18204439)
  6. Lehtinen MK et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell, 125(5):987-1001. (PMID 16751106)
  1. 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)
  2. Rinner O et al. An integrated mass spectrometric and computational framework for the analysis of protein interaction networks. Nat. Biotechnol., 25(3):345-52. (PMID 17322870)
  3. Bertoli C et al. Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A. Oncogene, 28(5):721-33. (PMID 19029949)
  4. Yamagata K et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell, 32(2):221-31. (PMID 18951090)
  5. van der Heide LP and Smidt MP. Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem. Sci., 30(2):81-6. (PMID 15691653)
  6. Jiang WJ. Sirtuins: novel targets for metabolic disease in drug development. Biochem. Biophys. Res. Commun., 373(3):341-4. (PMID 18577374)