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forkhead box protein O3A; forkhead in rhabdomyosarcoma-like 1 (FKHRL1, FOXO3A, FOXO3)

Function: - transcriptional activator - triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress - upregulates pro-apoptotic factor BCL2L11 - recognizes & binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' - interacts with YWHAB/14-3-3-beta & YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration - upon oxidative stress, interacts with STK4, which disrupts interaction with YWHAB/14-3-3-beta & leads to nuclear translocation. - AKT1 phosphorylates FKHRL1 in presence of survival factors including IGF-1, leading to association with 14-3-3 proteins & retention in cytoplasm - phosphorylated on Thr-32 & Ser-253 by AKT1/PKB - survival factor withdrawal induces dephosphorylation & promotes translocation to the nucleus where dephosphorylated protein induces transcription of target genes & triggers apoptosis - although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue - phosphorylated by STK4 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3beta & nuclear translocation - deacetylated by SIRT1 at Lys-271 which a) increases its ability to effect cell cycle arrest b) increases resistance to oxidative stress c) inhibits ability to induce cell death [4] - Lys-271 is methylated by Set9 [7,8] - leads to inhibition of its DNA-binding activity & transactivation [8] - reduces oxidative stress-induced and FOXO3-mediated Bim expression & neuronal apoptosis [8] - inhibited by TSC22D3 Structure: contains 1 fork-head DNA-binding domain Compartment: - cytoplasm - translocates to nucleus upon oxidative stress & in the absence of survival factors Expression: ubiquitous Pathology: - chromosomal translocation t(6;11)(q21;q23) involving FOXO3A with MLL/HRX is found in secondary acute leukemias Polymorphism: - SNPs of FOXO3A are associated with longevity in both men & women [6]

General

forkhead family transcription factor phosphoprotein

Properties

SIZE: MW = 71 kD entity length = 673 aa COMPARTMENT: cytoplasm cell nucleus MOTIF: Thr phosphorylation site {T32} fork head domain NAME: fork head domain SITE: 157-251 MOTIF: Ser phosphorylation site {S209} Ser phosphorylation site {S253} Ser phosphorylation site {S315}

References

  1. Brunet et al. Cell 96:857-68, 1999
  2. Entrez Gene :accession 2309
  3. UniProt :accession O43524
  4. Brunet A et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004, 303:2011-2015 PMID: 14976264
  5. Atlas of Genetics and Cytogenetics in Oncology and Haematology http://atlasgeneticsoncology.org/Genes/AF6q21ID125.html
  6. Li Y et al Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet. 2009 Dec 15;18(24):4897-904. PMID: 19793722
  7. Calnan DR et al Methylation by Set9 modulates FoxO3 stability and transcriptional activity. Aging (Albany NY). 2012 Jul 21. PMID: 22820736
  8. Xie Q et al Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep. 2012 Apr;13(4):371-7. PMID: 22402663

Databases & Figures

OMIM 602681 UniProt O43524 Entrez Gene 2309 Figures/diagrams/slides/tables related to forkhead box protein O3A