Biology:FOXO3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

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).[2] 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 [3]

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.[4]

FOXO3a also functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[5] or downregulation of anti-apoptotic proteins such as FLIP.[6]

Stem cells

Gopinath et al. (2014)[7] 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,[8] 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.[9]

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.[10] Plasma levels of β-hydroxybutyrate increase with fasting or a ketogenic diet.[11]

Association with longevity

Genetic variation in FOXO3 has been shown to be associated with healthspan and longevity in humans.[12] It is found in most centenarians across a variety of ethnic groups around the world.[13][14] 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

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.[15] Various types of tests had been used to measure intelligence.

See also

References

  1. ↑ "Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily". Genomics 47 (2): 187–199. January 1998. doi:10.1006/geno.1997.5122. PMID 9479491. 
  2. ↑ "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor". Cell 96 (6): 857–868. March 1999. doi:10.1016/S0092-8674(00)80595-4. PMID 10102273. 
  3. ↑ "FOXOs: signalling integrators for homeostasis maintenance". Nature Reviews. Molecular Cell Biology 14 (2): 83–97. February 2013. doi:10.1038/nrm3507. PMID 23325358. 
  4. ↑ "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. March 2018. doi:10.1161/ATVBAHA.117.310502. PMID 29326312. 
  5. ↑ "The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells". Blood 110 (9): 3209–3217. November 2007. doi:10.1182/blood-2007-02-073957. PMID 17634411. 
  6. ↑ "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. January 2004. doi:10.1074/jbc.M304736200. PMID 14551207. 
  7. ↑ "FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal". Stem Cell Reports 2 (4): 414–426. April 2014. doi:10.1016/j.stemcr.2014.02.002. PMID 24749067. 
  8. ↑ "The emerging roles of forkhead box (Fox) proteins in cancer". Nature Reviews. Cancer 7 (11): 847–859. November 2007. doi:10.1038/nrc2223. PMID 17943136. 
  9. ↑ "Entrez Gene: FOXO3A forkhead box O3A". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2309. 
  10. ↑ "Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor". Science 339 (6116): 211–214. January 2013. doi:10.1126/science.1227166. PMID 23223453. Bibcode: 2013Sci...339..211S. 
  11. ↑ "The neuropharmacology of the ketogenic diet". Pediatric Neurology 36 (5): 281–292. May 2007. doi:10.1016/j.pediatrneurol.2007.02.008. PMID 17509459. 
  12. ↑ "Multivariate genomic scan implicates novel loci and haem metabolism in human ageing". Nature Communications 11 (1): 3570. July 2020. doi:10.1038/s41467-020-17312-3. PMID 32678081. Bibcode: 2020NatCo..11.3570T. 
  13. ↑ "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. September 2008. doi:10.1073/pnas.0801030105. PMID 18765803. Bibcode: 2008PNAS..10513987W. 
  14. ↑ "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. February 2009. doi:10.1073/pnas.0809594106. PMID 19196970. Bibcode: 2009PNAS..106.2700F. 
  15. ↑ "Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence". Nature Genetics 49 (7): 1107–1112. July 2017. doi:10.1038/ng.3869. PMID 28530673. 

Further reading

External links

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



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