FOXO3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2K86, 2LQH, 2LQI, 2UZK
Identifiers
Aliases	FOXO3, AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A, forkhead box O3
External IDs	OMIM: 602681 MGI: 1890081 HomoloGene: 31039 GeneCards: FOXO3
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q21 Start 108,559,835 bp[1] End 108,684,774 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 B2|10 22.79 cM Start 42,057,837 bp[2] End 42,152,751 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte spongy bone cerebellar vermis nipple middle temporal gyrus visceral pleura tibialis anterior muscle pericardium parietal pleura amniotic fluid Top expressed in secondary oocyte ciliary body aortic valve ascending aorta cumulus cell blood fossa lacrimal gland medullary collecting duct left lung lobe More reference expression data BioGPS More reference expression data
Gene ontology Molecular function beta-catenin binding DNA-binding transcription activator activity, RNA polymerase II-specific protein binding protein kinase binding chromatin DNA binding DNA-binding transcription factor activity sequence-specific DNA binding DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific mitochondrial transcription factor activity transcription coregulator binding RNA polymerase II cis-regulatory region sequence-specific DNA binding transcription factor binding Cellular component membrane nucleoplasm cytosol cytoplasm nucleus mitochondrion mitochondrial outer membrane mitochondrial matrix protein-containing complex Biological process initiation of primordial ovarian follicle growth ovulation from ovarian follicle regulation of transcription, DNA-templated antral ovarian follicle growth positive regulation of erythrocyte differentiation glucose homeostasis DNA damage response, signal transduction by p53 class mediator tumor necrosis factor-mediated signaling pathway regulation of reactive oxygen species metabolic process transcription by RNA polymerase II regulation of neural precursor cell proliferation transcription, DNA-templated neuronal stem cell population maintenance positive regulation of neuron apoptotic process oocyte maturation extrinsic apoptotic signaling pathway in absence of ligand positive regulation of apoptotic process regulation of translation negative regulation of canonical Wnt signaling pathway apoptotic process negative regulation of transcription by RNA polymerase II regulation of transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II cellular response to oxidative stress positive regulation of transcription, DNA-templated positive regulation of reactive oxygen species biosynthetic process brain morphogenesis human ageing negative regulation of neuron differentiation cellular response to hypoxia response to water-immersion restraint stress response to nutrient levels cellular response to amyloid-beta cellular response to corticosterone stimulus positive regulation of endothelial cell apoptotic process positive regulation of hydrogen peroxide-mediated programmed cell death response to dexamethasone cellular response to nerve growth factor stimulus cellular response to glucose stimulus anatomical structure morphogenesis cytokine-mediated signaling pathway mitochondrial transcription negative regulation of cell migration insulin receptor signaling pathway positive regulation of autophagy positive regulation of muscle atrophy response to starvation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2309 56484 Ensembl ENSG00000118689 ENSMUSG00000048756 UniProt O43524 Q9WVH4 RefSeq (mRNA) NM_001455 NM_201559 NM_019740 NM_001376967 RefSeq (protein) NP_001446 NP_963853 NP_062714 NP_001363896 Location (UCSC) Chr 6: 108.56 – 108.68 Mb Chr 10: 42.06 – 42.15 Mb PubMed search [3] [4]
Wikidata
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Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.^[5]

Function

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]

Apoptosis

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

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

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

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. Mice lacking FOXO3 do not show obvious accelerated aging or shortened lifespan.

Association with intelligence

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

• FOX proteins
• Daf-16

References

Further reading

External links

• FOXO3A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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