FOXO3 belongs to the O subclass of theforkhead family oftranscription factors which are characterized by a distinctfork headDNA-binding domain. There are three other FoxO family members in humans,FOXO1,FOXO4 andFOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus onphosphorylation by proteins such asAkt/PKB in thePI3K 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 FOXO3aknockout 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 invascular smooth muscle cells induces prominentapoptosis andextracellular matrix breakdownin vitro and exacerbatesatherosclerosis and vascular remodellingin vivo. Also, these processes were at least partially dependent onMMP-13, as shown bysiRNA knockdown and specific pharmacological inhibition. Further experiments also revealed MMP-13 as a novel,bona fide transcriptional target gene of FOXO3a in VSMCs.[8]
It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such ascatalase andMnSOD.Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure.Gopinath et al., found that FOXO3 promotes quiescence of muscle stem cells during self-renewal in a Notch-dependent mechanism using muscle stem cell-specific conditional knock out mice. <Stem Cell Reports. 2014 Mar 20;2(4):414-26. doi: 10.1016/j.stemcr.2014.02.002>
Deregulation of FOXO3a is involved intumorigenesis,[11] for example translocation of this gene with theMLL gene is associated with secondary acuteleukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss ofPTEN). FOXO3 is known as a tumour suppressor.
Alternatively spliced transcript variants encoding the same protein have been observed.[12]
Genetic variation in FOXO3 has been shown to be associated withhealthspan andlongevity in humans.[15] It is found in mostcentenarians across a variety of ethnic groups around the world.[16][17] Thehomologous genesdaf-16 in thenematodeC. elegans anddFOXO in thefruit fly are also associated with longevity in those organisms.[18] Mice lacking FOXO3 do not show obvious accelerated aging or shortened lifespan.
In a meta-analysis of 78,308 individuals of European descent, a particularsingle 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.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.PMID9479491.
^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.PMID17943136.S2CID1330189.
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.PMID9479491.
DaSilva L, Kirken RA, Taub DD, Evans GA, Duhé RJ, Bailey MA, et al. (October 1998). "Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family".Gene.221 (1):135–142.doi:10.1016/S0378-1119(98)00441-7.PMID9852958.
Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A (February 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):1556–1562.doi:10.1038/sj.onc.1205230.PMID11896584.S2CID24537919.
Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, et al. (June 2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants".Molecular Vision.8:205–220.PMID12107410.
Charvet C, Alberti I, Luciano F, Jacquel A, Bernard A, Auberger P, et al. (July 2003). "Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases".Oncogene.22 (29):4557–4568.doi:10.1038/sj.onc.1206778.PMID12881712.S2CID11234589.
Crossley LJ (October 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".Journal of Leukocyte Biology.74 (4):583–592.doi:10.1189/jlb.0103020.PMID12960271.S2CID15199594.
