ID:FOXO3_HUMAN DESCRIPTION: RecName: Full=Forkhead box protein O3; AltName: Full=AF6q21 protein; AltName: Full=Forkhead in rhabdomyosarcoma-like 1; FUNCTION: Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post- transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation. SUBUNIT: Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration. Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Interacts with PIM1. Interacts with DDIT3/CHOP. INTERACTION: Q08050:FOXM1; NbExp=2; IntAct=EBI-1644164, EBI-866480; P51610:HCFC1; NbExp=2; IntAct=EBI-1644164, EBI-396176; Q96EB6:SIRT1; NbExp=5; IntAct=EBI-1644164, EBI-1802965; Q13485:SMAD4; NbExp=4; IntAct=EBI-1644164, EBI-347263; SUBCELLULAR LOCATION: Cytoplasm, cytosol. Nucleus. Note=Translocates to the nucleus upon oxidative stress and in the absence of survival factors. TISSUE SPECIFICITY: Ubiquitous. PTM: In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB. This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm. Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and 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/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Phosphorylated by PIM1. Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization. Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR- 34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation. PTM: Heavyly methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location. DISEASE: Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX. SIMILARITY: Contains 1 fork-head DNA-binding domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/AF6q21ID125.html";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O43524
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0001047 core promoter binding GO:0001221 transcription cofactor binding GO:0001227 transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0001228 transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0003677 DNA binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0005515 protein binding GO:0008013 beta-catenin binding GO:0019901 protein kinase binding GO:0031490 chromatin DNA binding GO:0034246 mitochondrial RNA polymerase binding promoter specificity activity GO:0043565 sequence-specific DNA binding
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0001542 ovulation from ovarian follicle GO:0001544 initiation of primordial ovarian follicle growth GO:0001547 antral ovarian follicle growth GO:0001556 oocyte maturation GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006357 regulation of transcription from RNA polymerase II promoter GO:0006366 transcription from RNA polymerase II promoter GO:0006390 transcription from mitochondrial promoter GO:0006417 regulation of translation GO:0006915 apoptotic process GO:0007568 aging GO:0009653 anatomical structure morphogenesis GO:0019221 cytokine-mediated signaling pathway GO:0030330 DNA damage response, signal transduction by p53 class mediator GO:0031667 response to nutrient levels GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0034599 cellular response to oxidative stress GO:0042493 response to drug GO:0042593 glucose homeostasis GO:0043065 positive regulation of apoptotic process GO:0043525 positive regulation of neuron apoptotic process GO:0045648 positive regulation of erythrocyte differentiation GO:0045665 negative regulation of neuron differentiation GO:0045893 positive regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0048854 brain morphogenesis GO:0071333 cellular response to glucose stimulus GO:0071386 cellular response to corticosterone stimulus GO:0071456 cellular response to hypoxia GO:0071548 response to dexamethasone GO:0090090 negative regulation of canonical Wnt signaling pathway GO:0097150 neuronal stem cell population maintenance GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand GO:1901300 positive regulation of hydrogen peroxide-mediated programmed cell death GO:1903428 positive regulation of reactive oxygen species biosynthetic process GO:1904646 cellular response to beta-amyloid GO:1990090 cellular response to nerve growth factor stimulus GO:1990785 response to water-immersion restraint stress GO:2000177 regulation of neural precursor cell proliferation GO:2000353 positive regulation of endothelial cell apoptotic process GO:2000377 regulation of reactive oxygen species metabolic process
JB406699 - Sequence 25 from Patent WO2012072685. LP896400 - Sequence 1264 from Patent EP3253886. BC020227 - Homo sapiens forkhead box O3, mRNA (cDNA clone MGC:31925 IMAGE:4111403), complete cds. BC021224 - Homo sapiens forkhead box O3, mRNA (cDNA clone MGC:12739 IMAGE:4137370), complete cds. AF032886 - Homo sapiens forkhead protein (FKHRL1) mRNA, complete cds. BC068552 - Homo sapiens forkhead box O3, mRNA (cDNA clone MGC:87459 IMAGE:30347471), complete cds. JB406698 - Sequence 24 from Patent WO2012072685. AK092357 - Homo sapiens cDNA FLJ35038 fis, clone OCBBF2016841, highly similar to FORKHEAD PROTEIN O3A. AJ001589 - Homo sapiens mRNA for fork head protein. AK122861 - Homo sapiens cDNA FLJ16486 fis, clone BRTHA3007532, moderately similar to Forkhead box protein O3A. CU676878 - Synthetic construct Homo sapiens gateway clone IMAGE:100023385 5' read FOXO3 mRNA. AB591039 - Synthetic construct DNA, clone: pFN21AB7063, Homo sapiens FOXO3 gene for forkhead box O3, without stop codon, in Flexi system. KJ891183 - Synthetic construct Homo sapiens clone ccsbBroadEn_00577 FOXO3 gene, encodes complete protein. AK311587 - Homo sapiens cDNA, FLJ18629. AK303933 - Homo sapiens cDNA FLJ52830 complete cds, highly similar to Forkhead box protein O3A. JD137057 - Sequence 118081 from Patent EP1572962. JD137058 - Sequence 118082 from Patent EP1572962. JD500445 - Sequence 481469 from Patent EP1572962. JD555872 - Sequence 536896 from Patent EP1572962. JD401746 - Sequence 382770 from Patent EP1572962. JD474989 - Sequence 456013 from Patent EP1572962. JD339371 - Sequence 320395 from Patent EP1572962. JD154055 - Sequence 135079 from Patent EP1572962. JD462600 - Sequence 443624 from Patent EP1572962. JD178134 - Sequence 159158 from Patent EP1572962. JD309120 - Sequence 290144 from Patent EP1572962. CR749261 - Homo sapiens mRNA; cDNA DKFZp781A0677 (from clone DKFZp781A0677). AK301304 - Homo sapiens cDNA FLJ53219 complete cds, highly similar to Forkhead box protein O3A. AF041336 - Homo sapiens fork head-like protein (FKHRL1P2) mRNA, complete cds. JD072505 - Sequence 53529 from Patent EP1572962. JD119239 - Sequence 100263 from Patent EP1572962. JD341147 - Sequence 322171 from Patent EP1572962. JD084286 - Sequence 65310 from Patent EP1572962. JD131242 - Sequence 112266 from Patent EP1572962. JD301783 - Sequence 282807 from Patent EP1572962. AB072905 - Homo sapiens primary neuroblastoma cDNA, clone:Nbla12092. AK024103 - Homo sapiens cDNA FLJ14041 fis, clone HEMBA1005780. BC045800 - Homo sapiens cDNA clone IMAGE:4814010. DQ572881 - Homo sapiens piRNA piR-40993, complete sequence. JD175731 - Sequence 156755 from Patent EP1572962. JD205223 - Sequence 186247 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_achPathway - Role of nicotinic acetylcholine receptors in the regulation of apoptosis h_ptenPathway - PTEN dependent cell cycle arrest and apoptosis h_longevityPathway - The IGF-1 Receptor and Longevity h_aktPathway - AKT Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein O43524 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
