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Foxo3 Information

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

Contents

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 signalling 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]

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,[5] 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 (eg 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.[6]

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.[7][8] 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

References

  1. ^ 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): 187–99. 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 (March 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 (November 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2200922.
  4. ^ Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (January 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. ^ Myatt SS, Lam EW (November 2007). "The emerging roles of forkhead box (Fox) proteins in cancer". Nat. Rev. Cancer 7 (11): 847–59. doi:10.1038/nrc2223. PMID 17943136.
  6. ^ "Entrez Gene: FOXO3A forkhead box O3A". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2309.
  7. ^ Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (September 2008). "FOXO3A genotype is strongly associated with human longevity". Proc. Natl. Acad. Sci. U.S.A. 105 (37): 13987–92. doi:10.1073/pnas.0801030105. PMC 2544566. PMID 18765803. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2544566.
  8. ^ Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (February 2009). "Association of FOXO3A variation with human longevity confirmed in German centenarians". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2700–5. doi:10.1073/pnas.0809594106. PMC 2650329. PMID 19196970. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2650329.

Further reading

External links

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

Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP) Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) · AP-1 (c-Fos, FOSB, FOSL1, FOSL2, JDP2, c-Jun, JUNB, JUND) · BACH (1, 2) · BATF · BLZF1 · C/EBP (α, β, γ, δ, ε, ζ) · CREB (1, 3, L1) · CREM · DBP · DDIT3 · GABPA · HLF · MAF (B, F, G, K) · NFE (2, L1, L2, L3) · NFIL3 · NRL · NRF (1, 2, 3) · XBP1
(1.2) Basic helix-loop-helix (bHLH) ATOH1 · AhR · AHRR · ARNT · ASCL1 · BHLHB2 · BMAL (ARNTL, ARNTL2) · CLOCK · EPAS1 · FIGLA · HAND (1, 2) · HES (5, 6) · HEY (1, 2, L) · HES1 · HIF (1A, 3A) · ID (1, 2, 3, 4) · LYL1 · MESP2 · MXD4 · MYCL1 · MYCN · Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) · Neurogenins (1, 2, 3) · NeuroD (1, 2) · NPAS (1, 2, 3) · OLIG (1, 2) · Pho4 · Scleraxis · SIM (1, 2) · TAL (1, 2) · Twist · USF1
(1.3) bHLH-ZIP AP-4 · MAX · MITF · MNT · MLX · MXI1 · Myc · SREBP (1, 2)
(1.4) NF-1 NFI (A, B, C, X) · SMAD (R-SMAD (1, 2, 3, 5, 9) - I-SMAD (6, 7) - 4)
(1.5) RF-X RFX (1, 2, 3, 4, 5, 6, ANK)
(1.6) Basic helix-span-helix (bHSH) AP-2 (α, β, γ, δ, ε)
(2) Zinc finger DNA-binding domains
(2.1) Nuclear receptor (Cys4) subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) subfamily 3 (Steroid hormone (Androgen, Estrogen (α, β), Glucocorticoid, Mineralocorticoid, Progesterone), Estrogen related (α, β, γ)) subfamily 4 NUR (NGFIB, NOR1, NURR1) · subfamily 5 (LRH-1, SF1) · subfamily 6 (GCNF) · subfamily 0 (DAX1, SHP)
(2.2) Other Cys4 GATA (1, 2, 3, 4, 5, 6) · MTA (1, 2, 3) · TRPS1
(2.3) Cys2His2 General transcription factors (TFIIA, TFIIB, TFIID, TFIIE (1, 2), TFIIF (1, 2), TFIIH (1, 2, 4, 2I, 3A, 3C1, 3C2)) ATBF1 · BCL (6, 11A, 11B) · CTCF · E4F1 · EGR (1, 2, 3, 4) · ERV3 · GFI1 · GLI-Krüppel family (1, 2, 3, REST, S2, YY1) · HIC (1, 2) · HIVEP (1, 2, 3) · IKZF (1, 2, 3) · ILF (2, 3) · KLF (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17) · MTF1 · MYT1 · OSR1 · PRDM9 · SALL (1, 2, 3, 4) · SP (1, 2, 4, 7, 8) · TSHZ3 · WT1 · Zbtb7 (7A, 7B) · ZBTB (11, 16, 17, 20, 32, 33, 40) · zinc finger (3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 300, 318, 330, 346, 350, 365, 366, 384, 423, 451, 452, 471, 593, 638, 644, 649, 655)
(2.4) Cys6 HIVEP1
(2.5) Alternating composition AIRE · DIDO1 · GRLF1 · ING (1, 2, 4) · JARID (1A, 1B, 1C, 1D, 2) · JMJD1B
(3) Helix-turn-helix domains
(3.1) Homeodomain ARX · CDX (1, 2) · CRX · CUTL1 · DBX (1, 2) · DLX (3, 4, 5) · EMX (1, 2) · EN (1, 2) · FHL (1, 2, 3) · HESX1 · HHEX · HLX · Homeobox (A1, A2, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C12, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) · HOPX · IRX (1, 2, 3, 4, 5, 6, MKX) · LMX (1A, 1B) · MEIS (1, 2) · MEOX2 · MNX1 · MSX (1, 2) · NANOG · NKX (2-1, 2-2, 2-3, 2-5, 3-1, 3-2, 6-1, 6-2) · NOBOX · PBX (1, 2, 3) · PHF (1, 3, 6, 8, 10, 16, 17, 20, 21A) · PHOX (2A, 2B) · PITX (1, 2, 3) · POU domain (PIT-1, BRN-3: A, B, C, Octamer transcription factor: 1, 2, 3/4, 6, 7, 11) · OTX (1, 2) · PDX1 · SATB2 · SHOX2 · VAX1 · ZEB (1, 2)
(3.2) Paired box PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
(3.3) Fork head / winged helix E2F (1, 2, 3, 4, 5) · FOX proteins (A1, A2, A3, C1, C2, D3, D4, E1, E3, F1, G1, H1, I1, J1, J2, K1, K2, L2, M1, N1, N3, O1, O3, O4, P1, P2, P3, P4)
(3.4) Heat Shock Factors HSF (1, 2, 4)
(3.5) Tryptophan clusters ELF (2, 4, 5) · EGF · ELK (1, 3, 4) · ERF · ETS (1, 2, ERG, SPIB) · ETV (1, 4, 5, 6) · FLI1 · Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) · MYB · MYBL2
(3.6) TEA domain transcriptional enhancer factor (1, 2, 3, 4)
(4) β-Scaffold factors with minor groove contacts
(4.1) Rel homology region NF-κB (NFKB1, NFKB2, REL, RELA, RELB) · NFAT (C1, C2, C3, C4, 5)
(4.2) STAT STAT (1, 2, 3, 4, 5, 6)
(4.3) p53 p53 · TBX (1, 2, 3, 5, 19, 21, 22, Brachyury, TBR1, TBR2) · TP63
(4.4) MADS box Mef2 (A, B, C, D) · SRF
(4.6) TATA binding proteins TBP · TBPL1
(4.7) High-mobility group BBX · HMGB (1, 2, 3, 4) · HMGN (1, 2, 3, 4) · HNF (1A, 1B) · LEF1 · SOX (1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 18, 21) · SRY · SSRP1 · TCF (3, 4) · TOX (1, 2, 3, 4)
(4.10) Cold-shock domain CSDA, YBX1
(4.11) Runt CBF (CBFA2T2, CBFA2T3, RUNX1, RUNX2, RUNX3, RUNX1T1)
Other transcription factors
(0.2) HMGI(Y) HMGA (1, 2) · HBP1
(0.3) Pocket domain Rb · RBL1 · RBL2
(0.5) AP-2/EREBP-related factors Apetala 2 · EREBP · B3
(0.6) Miscellaneous ARID (1A, 1B, 2, 3A, 3B, 4A) · CAP · IFI (16, 35) · MLL (2, 3, T1) · MNDA · NFY (A, B, C) · Rho/Sigma
see also : dna (, , , ) · (, , , , , ) · (, , ) · , / · stru (, , , , )
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