Human Gene FOXO3 (ENST00000406360.2_4) from GENCODE V45lift37
Description: Homo sapiens forkhead box O3 (FOXO3), transcript variant 1, mRNA. (from RefSeq NM_001455) RefSeq Summary (NM_001455): This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]. Gencode Transcript: ENST00000406360.2_4 Gencode Gene: ENSG00000118689.15_7 Transcript (Including UTRs) Position: hg19 chr6:108,882,120-109,005,977 Size: 123,858 Total Exon Count: 3 Strand: + Coding Region Position: hg19 chr6:108,882,412-108,986,058 Size: 103,647 Coding Exon Count: 2
ID:FOXO3_HUMAN DESCRIPTION: RecName: Full=Forkhead box protein O3 ; AltName: Full=AF6q21 protein ; AltName: Full=Forkhead in rhabdomyosarcoma-like 1 ; FUNCTION: Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882, PubMed:30513302). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). 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 (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3 (PubMed:30513302). SUBUNIT: Upon metabolic stress, forms a complex composed of FOXO3, SIRT3 and mitochondrial RNA polymerase POLRMT; the complex is recruited to mtDNA in a SIRT3-dependent manner (PubMed:23283301). Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT (PubMed:29445193). Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity (By similarity). Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration (PubMed:16751106). Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation (PubMed:16751106). Interacts with PIM1 (PubMed:18593906). Interacts with DDIT3/CHOP (PubMed:22761832). Interacts (deacetylated form) with SKP2 (PubMed:21841822). Interacts with CHUK and IKBKB (PubMed:15084260, PubMed:22313691). Interacts with CAMK2A, CAMK2B and calcineurin A (By similarity). Interacts with NUPR1; this interaction represses FOXO3 transactivation (PubMed:20181828). INTERACTION: O43524; P31749: AKT1; NbExp=3; IntAct=EBI-1644164, EBI-296087; O43524; Q92974: ARHGEF2; NbExp=2; IntAct=EBI-1644164, EBI-302405; O43524; P30260: CDC27; NbExp=2; IntAct=EBI-1644164, EBI-994813; O43524; Q92793: CREBBP; NbExp=3; IntAct=EBI-1644164, EBI-81215; O43524; P03372: ESR1; NbExp=7; IntAct=EBI-1644164, EBI-78473; O43524; Q92731: ESR2; NbExp=4; IntAct=EBI-1644164, EBI-78505; O43524; P85037: FOXK1; NbExp=2; IntAct=EBI-1644164, EBI-2509974; O43524; Q08050: FOXM1; NbExp=2; IntAct=EBI-1644164, EBI-866480; O43524; P51610: HCFC1; NbExp=2; IntAct=EBI-1644164, EBI-396176; O43524; P01106: MYC; NbExp=3; IntAct=EBI-1644164, EBI-447544; O43524; P11309-1: PIM1; NbExp=2; IntAct=EBI-1644164, EBI-1018629; O43524; Q96T60: PNKP; NbExp=2; IntAct=EBI-1644164, EBI-1045072; O43524; P06400: RB1; NbExp=2; IntAct=EBI-1644164, EBI-491274; O43524; P28749: RBL1; NbExp=3; IntAct=EBI-1644164, EBI-971402; O43524; P31947: SFN; NbExp=3; IntAct=EBI-1644164, EBI-476295; O43524; Q96EB6: SIRT1; NbExp=5; IntAct=EBI-1644164, EBI-1802965; O43524; P84022: SMAD3; NbExp=5; IntAct=EBI-1644164, EBI-347161; O43524; Q13485: SMAD4; NbExp=9; IntAct=EBI-1644164, EBI-347263; O43524; O75529: TAF5L; NbExp=2; IntAct=EBI-1644164, EBI-1785876; O43524; P62258: YWHAE; NbExp=4; IntAct=EBI-1644164, EBI-356498; O43524; P63104: YWHAZ; NbExp=4; IntAct=EBI-1644164, EBI-347088; O43524; Q60987: Foxg1; Xeno; NbExp=5; IntAct=EBI-1644164, EBI-11166131; O43524; P63101: Ywhaz; Xeno; NbExp=2; IntAct=EBI-1644164, EBI-354751; SUBCELLULAR LOCATION: Cytoplasm, cytosol cleus Mitochondrion matrix tochondrion outer membrane ; Peripheral membrane protein ; Cytoplasmic side Note=Retention in the cytoplasm contributes to its inactivation (PubMed:10102273, PubMed:15084260, PubMed:16751106). Translocates to the nucleus upon oxidative stress and in the absence of survival factors (PubMed:10102273, PubMed:16751106). Translocates from the cytosol to the nucleus following dephosphorylation in response to autophagy-inducing stimuli (By similarity). Translocates in a AMPK-dependent manner into the mitochondrion in response to metabolic stress (PubMed:23283301, PubMed:29445193). Serum deprivation increases localization to the nucleus, leading to activate expression of SOX9 and subsequent chondrogenesis (By similarity). TISSUE SPECIFICITY: Ubiquitous. PTM: In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-253 by AKT1/PKB (PubMed:10102273). This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm (PubMed:10102273). Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis (PubMed:10102273). Although AKT1/PKB doesn't appear to phosphorylate Ser-315 directly, it may activate other kinases that trigger phosphorylation at this residue (PubMed:10102273, PubMed:11154281). Phosphorylated by STK4/MST1 on Ser-209 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation (PubMed:16751106). Phosphorylated by PIM1 (PubMed:18593906). Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization (PubMed:17711846). In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation (PubMed:29445193). 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 (PubMed:21329882). Phosphorylated by CHUK/IKKA and IKBKB/IKKB (PubMed:15084260). TNF-induced inactivation of FOXO3 requires its phosphorylation at Ser-644 by IKBKB/IKKB which promotes FOXO3 retention in the cytoplasm, polyubiquitination and ubiquitin-mediated proteasomal degradation (PubMed:15084260). May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity (By similarity). In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents (PubMed:29445193). Phosphorylation at Ser-253 promotes its degradation by the proteasome (PubMed:30513302). Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:30513302). PTM: Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (PubMed:21841822). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress (By similarity). Deacetylated by SIRT3 (PubMed:23283301). Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress (PubMed:23283301). PTM: Heavily methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-271. Methylation doesn't affect subcellular location. PTM: Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation. PTM: The N-terminus is cleaved following import into the mitochondrion. DISEASE: Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="https://atlasgeneticsoncology.org/gene/125/AF6q21";
Cholesterol, HDL Sekar Kathiresan et al. BMC medical genetics 2007, A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study., BMC medical genetics.
[PubMed 17903299]
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
Electrocardiography Christopher Newton-Cheh et al. BMC medical genetics 2007, Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study., BMC medical genetics.
[PubMed 17903306]
In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.
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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Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA 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:0008134 transcription factor 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:0006355 regulation of transcription, DNA-templated GO:0006357 regulation of 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:0008286 insulin receptor signaling pathway GO:0010508 positive regulation of autophagy GO:0014737 positive regulation of muscle atrophy GO:0019221 cytokine-mediated signaling pathway GO:0030330 DNA damage response, signal transduction by p53 class mediator GO:0030336 negative regulation of cell migration 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:0042594 response to starvation 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