FOXO3

Forkhead box O3
Rendering based on PDB 2K86​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2K86​, 2LQH​, 2LQI​, 2UZK​
Identifiers
Symbols	FOXO3 ; AF6q21; FKHRL1; FKHRL1P2; FOXO2; FOXO3A
External IDs	OMIM: 602681 MGI: 1890081 HomoloGene: 31039 ChEMBL: 5778 GeneCards: FOXO3 Gene
Gene ontology Molecular function • RNA polymerase II transcription factor activity, sequence-specific DNA binding • core promoter binding • transcription cofactor binding • transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • protein kinase binding • chromatin DNA binding • sequence-specific DNA binding Cellular component • nucleus • nucleoplasm • cytoplasm • cytosol • membrane Biological process • negative regulation of transcription from RNA polymerase II promoter • ovulation from ovarian follicle • initiation of primordial ovarian follicle growth • antral ovarian follicle growth • oocyte maturation • transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • regulation of translation • epidermal growth factor receptor signaling pathway • fibroblast growth factor receptor signaling pathway • anatomical structure morphogenesis • cell differentiation • DNA damage response, signal transduction by p53 class mediator • cellular response to oxidative stress • Fc-epsilon receptor signaling pathway • glucose homeostasis • positive regulation of neuron apoptotic process • innate immune response • positive regulation of erythrocyte differentiation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • negative regulation of canonical Wnt signaling pathway • neuronal stem cell maintenance • extrinsic apoptotic signaling pathway in absence of ligand • regulation of neural precursor cell proliferation • regulation of reactive oxygen species metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
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: 108.56 – 108.68 Mb	Chr 10: 42.18 – 42.28 Mb
PubMed search

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.

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

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

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

• FOX proteins
• Daf-16

References

1. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (Jan 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 (Mar 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 (Nov 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 (Jan 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 SD, Webb AE, Brunet A, Rando TA (Apr 2014). "FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal". Stem Cell Reports 2 (4): 414–26. doi:10.1016/j.stemcr.2014.02.002. PMID 24749067.
6. Myatt SS, Lam EW (Nov 2007). "The emerging roles of forkhead box (Fox) proteins in cancer". Nature Reviews. 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 (Sep 2008). "FOXO3A genotype is strongly associated with human longevity". Proceedings of the National Academy of Sciences of the United States of America 105 (37): 13987–92. 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 (Feb 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): 2700–5. doi:10.1073/pnas.0809594106. PMC 2650329. PMID 19196970.

Further reading

• Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, Medema RH (May 2002). "The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2". Journal of Immunology 168 (10): 5024–5031. doi:10.4049/jimmunol.168.10.5024. PMID 11994454.
• Morris BJ, Willcox DC, Donlon TA, Willcox BJ (Mar 2015). "FOXO3: A Major Gene for Human Longevity - A Mini-Review". Gerontology 61: 515–25. doi:10.1159/000375235. PMID 25832544.
• Kino T, Chrousos GP (Jun 2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Annals of the New York Academy of Sciences 1024: 153–67. doi:10.1196/annals.1321.013. PMID 15265780.
• Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA (Nov 1997). "AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily". Blood 90 (9): 3714–9. PMID 9345057.
• Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (Jan 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.
• DaSilva L, Kirken RA, Taub DD, Evans GA, Duhé RJ, Bailey MA, Farrar WL (Oct 1998). "Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family". Gene 221 (1): 135–42. doi:10.1016/S0378-1119(98)00441-7. PMID 9852958.
• Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (Mar 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.
• Medema RH, Kops GJ, Bos JL, Burgering BM (Apr 2000). "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1". Nature 404 (6779): 782–7. doi:10.1038/35008115. PMID 10783894.
• Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME (Feb 2001). "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)". Molecular and Cellular Biology 21 (3): 952–65. doi:10.1128/MCB.21.3.952-965.2001. PMC 86685. PMID 11154281.
• Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ (Sep 2001). "Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family". The Journal of Biological Chemistry 276 (36): 33554–60. doi:10.1074/jbc.M105555200. PMID 11435445.
• Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM (Apr 2002). "Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors". Molecular and Cellular Biology 22 (7): 2025–36. doi:10.1128/MCB.22.7.2025-2036.2002. PMC 133681. PMID 11884591.
• Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A (Feb 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): 1556–62. doi:10.1038/sj.onc.1205230. PMID 11896584.
• Nadal A, Marrero PF, Haro D (Aug 2002). "Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1". The Biochemical Journal 366 (Pt 1): 289–97. doi:10.1042/BJ20020598. PMC 1222772. PMID 12027802.
• Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (Jun 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: 205–20. PMID 12107410.
• Modur V, Nagarajan R, Evers BM, Milbrandt J (Dec 2002). "FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer". The Journal of Biological Chemistry 277 (49): 47928–37. doi:10.1074/jbc.M207509200. PMID 12351634.
• Charvet C, Alberti I, Luciano F, Jacquel A, Bernard A, Auberger P, Deckert M (Jul 2003). "Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases". Oncogene 22 (29): 4557–68. doi:10.1038/sj.onc.1206778. PMID 12881712.
• Crossley LJ (Oct 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): 583–92. doi:10.1189/jlb.0103020. PMID 12960271.
• Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC, Lam EW (Dec 2003). "FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines". The Journal of Biological Chemistry 278 (50): 49795–805. doi:10.1074/jbc.M309523200. PMID 14527951.
• Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (Jan 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.
• Dansen TB, Kops GJ, Denis S, Jelluma N, Wanders RJ, Bos JL, Burgering BM, Wirtz KW (Jan 2004). "Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a". Journal of Lipid Research 45 (1): 81–8. doi:10.1194/jlr.M300111-JLR200. PMID 14563822.

External links

• FOXO3A protein, human at the US 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.