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Title: Foxo3  
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Subject: Ageing, Epigenetics and melanoma, Longevity, ERIBA, List of Jamaican supercentenarians
Collection: Aging-Related Proteins, Forkhead Transcription Factors
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Forkhead box O3

Rendering based on PDB .
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; AF6q21; FKHRL1; FKHRL1P2; FOXO2; FOXO3A
External IDs ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.[1]


  • Function 1
  • Clinical significance 2
  • Association with longevity 3
  • See also 4
  • References 5
  • Further reading 6
  • External links 7


FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear).[2] Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.

This protein likely functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[3] or downregulation of anti-apoptotic proteins such as FLIP.[4]

Gopinath et al.(2014)[5] demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration.

It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.

Clinical significance

Deregulation of FOXO3a is involved in tumorigenesis,[6] for example translocation of this gene with the MLL gene is associated with secondary acute leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor.

Alternatively spliced transcript variants encoding the same protein have been observed.[7]

Association with longevity

A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[8][9] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms.

See also


  1. ^ Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (January 1998). "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily". Genomics 47 (2): 187–99.  
  2. ^ Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (March 1999). "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor". Cell 96 (6): 857–68.  
  3. ^ Ekoff M, Kaufmann T, Engström M, Motoyama N, Villunger A, Jönsson JI, Strasser A, Nilsson G (November 2007). "The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells". Blood 110 (9): 3209–17.  
  4. ^ Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (January 2004). "The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP". The Journal of Biological Chemistry 279 (2): 1513–25.  
  5. ^ Gopinath S. D. , Webb A. E. , Brunet A., Rando T. A. (2014). FOXO3 Promotes Quiescence in Adult Muscle Stem Cells during the Process of Self-Renewal. Stem Cell Reports, doi:10.1016/j.stemcr.2014.02.002
  6. ^ Myatt SS, Lam EW (November 2007). "The emerging roles of forkhead box (Fox) proteins in cancer". Nat. Rev. Cancer 7 (11): 847–59.  
  7. ^ "Entrez Gene: FOXO3A forkhead box O3A". 
  8. ^ Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (September 2008). "FOXO3A genotype is strongly associated with human longevity". Proc. Natl. Acad. Sci. U.S.A. 105 (37): 13987–92.  
  9. ^ Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (February 2009). "Association of FOXO3A variation with human longevity confirmed in German centenarians". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2700–5.  

Further reading

  • Stahl M, et al. (2002). "The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2.". J. Immunol 168 (10): 5024–5031.  
  • Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024: 153–67.  
  • Hillion J, Le Coniat M, Jonveaux P, et al. (1997). "AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily.". Blood 90 (9): 3714–9.  
  • Anderson MJ, Viars CS, Czekay S, et al. (1998). "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily.". Genomics 47 (2): 187–99.  
  • DaSilva L, Kirken RA, Taub DD, et al. (1998). "Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family.". Gene 221 (1): 135–42.  
  • Brunet A, Bonni A, Zigmond MJ, et al. (1999). "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.". Cell 96 (6): 857–68.  
  • Medema RH, Kops GJ, Bos JL, Burgering BM (2000). "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.". Nature 404 (6779): 782–7.  
  • Brunet A, Park J, Tran H, et al. (2001). "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a).". Mol. Cell. Biol. 21 (3): 952–65.  
  • Schuur ER, Loktev AV, Sharma M, et al. (2001). "Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family.". J. Biol. Chem. 276 (36): 33554–60.  
  • Kops GJ, Medema RH, Glassford J, et al. (2002). "Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.". Mol. Cell. Biol. 22 (7): 2025–36.  
  • Mahmud DL, G-Amlak M, Deb DK, et al. (2002). "Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells.". Oncogene 21 (10): 1556–62.  
  • Nadal A, Marrero PF, Haro D (2002). "Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1.". Biochem. J. 366 (Pt 1): 289–97.  
  • Wistow G, Bernstein SL, Wyatt MK, et al. (2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants.". Mol. Vis. 8: 205–20.  
  • Modur V, Nagarajan R, Evers BM, Milbrandt J (2003). "FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer.". J. Biol. Chem. 277 (49): 47928–37.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • Charvet C, Alberti I, Luciano F, et al. (2003). "Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases.". Oncogene 22 (29): 4557–68.  
  • Crossley LJ (2003). "Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1.". J. Leukoc. Biol. 74 (4): 583–92.  
  • Sunters A, Fernández de Mattos S, Stahl M, et al. (2004). "FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines.". J. Biol. Chem. 278 (50): 49795–805.  
  • Skurk C, Maatz H, Kim HS, et al. (2004). "The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP.". J. Biol. Chem. 279 (2): 1513–25.  
  • Dansen TB, Kops GJ, Denis S, et al. (2004). "Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a.". J. Lipid Res. 45 (1): 81–8.  
  • Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6.". Nature 425 (6960): 805–11.  

External links

  • FOXO3A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Transcription Factor encyclopedia entry for FOXO3

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