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 • DNA binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity • protein binding • transcription factor binding • DNA binding, bending • protein kinase binding • sequence-specific DNA binding Cellular component • nucleus • nucleoplasm • transcription factor complex • cytoplasm • cytosol 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 • regulation of translation • apoptotic process • induction of apoptosis • response to stress • response to DNA damage stimulus • epidermal growth factor receptor signaling pathway • pattern specification process • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • embryo development • tissue development • DNA damage response, signal transduction by p53 class mediator • regulation of cell proliferation • glucose homeostasis • positive regulation of erythrocyte differentiation • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • nerve growth factor receptor signaling pathway • phosphatidylinositol-mediated signaling • regulation of sequence-specific DNA binding transcription factor activity 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: 108.88 – 109.01 Mb	Chr 10: 42.18 – 42.28 Mb
PubMed search	[1]	[2]

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

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). 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, or downregulation of anti-apoptotic proteins such as FLIP.

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, 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.

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. 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

Further readings

• Stahl M, et al. (2002). "The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2.". J. Immunol 168 (10): 5024–5031. PMID 11994454. 
• Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024: 153–67. doi:10.1196/annals.1321.013. PMID 15265780. 
• Hillion J, Le Coniat M, Jonveaux P, et al. (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, et al. (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, et al. (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, et al. (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 (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, et al. (2001). "Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a).". Mol. Cell. Biol. 21 (3): 952–65. doi:10.1128/MCB.21.3.952-965.2001. PMC 86685. PMID 11154281. 
• Schuur ER, Loktev AV, Sharma M, et al. (2001). "Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family.". J. Biol. Chem. 276 (36): 33554–60. doi:10.1074/jbc.M105555200. PMID 11435445. 
• Kops GJ, Medema RH, Glassford J, et al. (2002). "Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors.". Mol. Cell. Biol. 22 (7): 2025–36. doi:10.1128/MCB.22.7.2025-2036.2002. PMC 133681. PMID 11884591. 
• Mahmud DL, G-Amlak M, Deb DK, et al. (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 (2002). "Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1.". Biochem. J. 366 (Pt 1): 289–97. doi:10.1042/BJ20020598. PMC 1222772. PMID 12027802. 
• Wistow G, Bernstein SL, Wyatt MK, et al. (2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants.". Mol. Vis. 8: 205–20. PMID 12107410. 
• Modur V, Nagarajan R, Evers BM, Milbrandt J (2003). "FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer.". J. Biol. Chem. 277 (49): 47928–37. doi:10.1074/jbc.M207509200. PMID 12351634. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. 
• Charvet C, Alberti I, Luciano F, et al. (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 (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.". J. Leukoc. Biol. 74 (4): 583–92. doi:10.1189/jlb.0103020. PMID 12960271. 
• Sunters A, Fernández de Mattos S, Stahl M, et al. (2004). "FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines.". J. Biol. Chem. 278 (50): 49795–805. doi:10.1074/jbc.M309523200. PMID 14527951. 
• Skurk C, Maatz H, Kim HS, et al. (2004). "The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP.". J. Biol. Chem. 279 (2): 1513–25. doi:10.1074/jbc.M304736200. PMID 14551207. 
• Dansen TB, Kops GJ, Denis S, et al. (2004). "Regulation of sterol carrier protein gene expression by the forkhead transcription factor FOXO3a.". J. Lipid Res. 45 (1): 81–8. doi:10.1194/jlr.M300111-JLR200. PMID 14563822. 
• Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6.". Nature 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404. 

External links

• FOXO3A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=443 Transcription Factor encyclopedia entry for FOXO3

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