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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Isoforms

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].

References
  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].

References
  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)