forkhead box protein O3A; forkhead in rhabdomyosarcoma-like 1 (FKHRL1, FOXO3A, FOXO3)
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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
- increases its ability to effect cell cycle arrest
- increases resistance to oxidative stress
- inhibits ability to induce cell death[4]
- Lys-271 is methylated by Set9[7][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
Pathology
- chromosomal translocation t(6;11)(q21;q23) involving FOXO3A with MLL/HRX is found in secondary acute leukemias
Polymorphism
More general terms
References
- ↑ Brunet et al. Cell 96:857-68, 1999
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=2309
- ↑ UniProt http://www.uniprot.org/uniprot/O43524.html
- ↑ 4.0 4.1 Brunet A et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004, 303:2011-2015 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14976264
- ↑ Atlas of Genetics and Cytogenetics in Oncology and Haematology http://atlasgeneticsoncology.org/Genes/AF6q21ID125.html
- ↑ 6.0 6.1 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: https://www.ncbi.nlm.nih.gov/pubmed/19793722
- ↑ 7.0 7.1 Calnan DR et al Methylation by Set9 modulates FoxO3 stability and transcriptional activity. Aging (Albany NY). 2012 Jul 21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22820736
- ↑ 8.0 8.1 8.2 8.3 Xie Q et al Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep. 2012 Apr;13(4):371-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22402663