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Available structures
PDBOrtholog search: PDBe RCSB
AliasesFOXO3, AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A, forkhead box O3
External IDsOMIM: 602681 MGI: 1890081 HomoloGene: 31039 GeneCards: FOXO3
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 6: 108.56 – 108.68 MbChr 10: 42.06 – 42.15 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.[5]


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).[6] Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.

The use of FOXO3a knockout mice has revealed a diverse range of functions in both health and disease, namely infertility, lymphoproliferation, adenoma, organ inflammation, metabolism etc.; yet despite the purported importance of FOXO transcription factors in aging, FOXO3A knockout mice do not show an obvious shortening of lifespan or accelerated aging [7]


Yu & Fellows et al. (2018) demonstrated that FOXO3a activation in vascular smooth muscle cells induces prominent apoptosis and extracellular matrix breakdown in vitro and exacerbates atherosclerosis and vascular remodelling in vivo. Also, these processes were at least partially dependent on MMP-13, as shown by siRNA knockdown and specific pharmacological inhibition. Further experiments also revealed MMP-13 as a novel, bona fide transcriptional target gene of FOXO3a in VSMCs.[8]

FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[9] or downregulation of anti-apoptotic proteins such as FLIP.[10]

Stem cells[edit]

Gopinath et al. (2014)[11] 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,[12] 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.[13]

The ketone body β-hydroxybutyrate has been shown in mice to increase gene expression of FOXO3a by histone deacetylase inhibition, upon which FOXO3a transcriptionally increased gene expression of the antioxidant enzymes SOD2 and catalase.[14] Plasma levels of β-hydroxybutyrate increase with fasting or a ketogenic diet.[15]

Association with longevity[edit]

Genetic variation in FOXO3 has been shown to be associated with healthspan and longevity in humans.[16] It is found in most centenarians across a variety of ethnic groups around the world.[17][18] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms.[citation needed] Mice lacking FOXO3 do not show obvious accelerated aging or shortened lifespan.

Association with intelligence[edit]

In a meta-analysis of 78,308 individuals of European descent, a particular single nucleotide polymorphism (SNP) (rs2490272) in an intronic region of FOXO3 and neighboring SNPs in the promoter region, had the strongest associations with intelligence.[19] Various types of tests had been used to measure intelligence.

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000118689 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000048756 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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): 187–199. doi:10.1006/geno.1997.5122. PMID 9479491.
  6. ^ Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. (March 1999). "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor". Cell. 96 (6): 857–868. doi:10.1016/S0092-8674(00)80595-4. PMID 10102273. S2CID 14506473.
  7. ^ Eijkelenboom A, Burgering BM (February 2013). "FOXOs: signalling integrators for homeostasis maintenance". Nature Reviews. Molecular Cell Biology. 14 (2): 83–97. doi:10.1038/nrm3507. PMID 23325358. S2CID 39922160.
  8. ^ Yu H, Fellows A, Foote K, Yang Z, Figg N, Littlewood T, Bennett M (March 2018). "FOXO3a (Forkhead Transcription Factor O Subfamily Member 3a) Links Vascular Smooth Muscle Cell Apoptosis, Matrix Breakdown, Atherosclerosis, and Vascular Remodeling Through a Novel Pathway Involving MMP13 (Matrix Metalloproteinase 13)". Arteriosclerosis, Thrombosis, and Vascular Biology. 38 (3): 555–565. doi:10.1161/ATVBAHA.117.310502. PMC 5828387. PMID 29326312.
  9. ^ Ekoff M, Kaufmann T, Engström M, Motoyama N, Villunger A, Jönsson JI, et al. (November 2007). "The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells". Blood. 110 (9): 3209–3217. doi:10.1182/blood-2007-02-073957. PMC 2200922. PMID 17634411.
  10. ^ 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): 1513–1525. doi:10.1074/jbc.M304736200. PMID 14551207.
  11. ^ Gopinath SD, Webb AE, Brunet A, Rando TA (April 2014). "FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal". Stem Cell Reports. 2 (4): 414–426. doi:10.1016/j.stemcr.2014.02.002. PMC 3986584. PMID 24749067.
  12. ^ Myatt SS, Lam EW (November 2007). "The emerging roles of forkhead box (Fox) proteins in cancer". Nature Reviews. Cancer. 7 (11): 847–859. doi:10.1038/nrc2223. PMID 17943136. S2CID 1330189.
  13. ^ "Entrez Gene: FOXO3A forkhead box O3A".
  14. ^ Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. (January 2013). "Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor". Science. 339 (6116): 211–214. Bibcode:2013Sci...339..211S. doi:10.1126/science.1227166. PMC 3735349. PMID 23223453.
  15. ^ Hartman AL, Gasior M, Vining EP, Rogawski MA (May 2007). "The neuropharmacology of the ketogenic diet". Pediatric Neurology. 36 (5): 281–292. doi:10.1016/j.pediatrneurol.2007.02.008. PMC 1940242. PMID 17509459.
  16. ^ Timmers PR, Wilson JF, Joshi PK, Deelen J (July 2020). "Multivariate genomic scan implicates novel loci and haem metabolism in human ageing". Nature Communications. 11 (1): 3570. Bibcode:2020NatCo..11.3570T. doi:10.1038/s41467-020-17312-3. PMC 7366647. PMID 32678081.
  17. ^ Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, et al. (September 2008). "FOXO3A genotype is strongly associated with human longevity". Proceedings of the National Academy of Sciences of the United States of America. 105 (37): 13987–13992. Bibcode:2008PNAS..10513987W. doi:10.1073/pnas.0801030105. PMC 2544566. PMID 18765803.
  18. ^ Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, et al. (February 2009). "Association of FOXO3A variation with human longevity confirmed in German centenarians". Proceedings of the National Academy of Sciences of the United States of America. 106 (8): 2700–2705. Bibcode:2009PNAS..106.2700F. doi:10.1073/pnas.0809594106. PMC 2650329. PMID 19196970.
  19. ^ Sniekers S, Stringer S, Watanabe K, Jansen PR, Coleman JR, Krapohl E, et al. (July 2017). "Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence". Nature Genetics. 49 (7): 1107–1112. doi:10.1038/ng.3869. PMC 5665562. PMID 28530673.

Further reading[edit]

External links[edit]

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