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Forkhead box O3
Protein FOXO3 PDB 2K86.png
Rendering based on PDB 2K86.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols FOXO3 ; AF6q21; FKHRL1; FKHRL1P2; FOXO2; FOXO3A
External IDs OMIM602681 MGI1890081 HomoloGene31039 ChEMBL: 5778 GeneCards: FOXO3 Gene
RNA expression pattern
PBB GE FOXO3A 204131 s at tn.png
PBB GE FOXO3A 204132 s at tn.png
PBB GE FOXO3A 210655 s at tn.png
More reference expression data
Species Human Mouse
Entrez 2309 56484
Ensembl ENSG00000118689 ENSMUSG00000048756
UniProt O43524 Q9WVH4
RefSeq (mRNA) NM_001455 NM_019740
RefSeq (protein) NP_001446 NP_062714
Location (UCSC) Chr 6:
108.88 – 109.01 Mb
Chr 10:
42.18 – 42.28 Mb
PubMed search [1] [2]

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


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[edit]

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[edit]

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[edit]


  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. doi:10.1006/geno.1997.5122. PMID 9479491. 
  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. doi:10.1016/S0092-8674(00)80595-4. PMID 10102273. 
  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. doi:10.1182/blood-2007-02-073957. PMC 2200922. PMID 17634411. 
  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. doi:10.1074/jbc.M304736200. PMID 14551207. 
  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. doi:10.1038/nrc2223. PMID 17943136. 
  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. doi:10.1073/pnas.0801030105. PMC 2544566. PMID 18765803. 
  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. doi:10.1073/pnas.0809594106. PMC 2650329. PMID 19196970. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.