FOXO3

Summary

FOXO3 (forkhead box O3, HGNC:3821) is a protein-coding gene on chromosome 6q21, encoding Forkhead box protein O3 (O43524). 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. It is a selective cancer dependency (DepMap: 18.6% of cell lines).

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.

Source: NCBI Gene 2309 — RefSeq curated summary.

At a glance

• GWAS associations: 66
• Clinical variants (ClinVar): 102 total
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 18.6% of screened cell lines
• Transcription factor: yes — 206 downstream targets (CollecTRI)
• MANE Select transcript: NM_001455

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3821
Approved symbol	FOXO3
Name	forkhead box O3
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	AF6q21, FOXO2
Ensembl gene	ENSG00000118689
Ensembl biotype	protein_coding
OMIM	602681
Entrez	2309

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000343882, ENST00000406360, ENST00000540898, ENST00000898147, ENST00000898148, ENST00000898149, ENST00000898150, ENST00000918253, ENST00000963984, ENST00000963985, ENST00000963986

RefSeq mRNA: 12 — MANE Select: NM_001455 NM_001415139, NM_001415140, NM_001415142, NM_001415144, NM_001415145, NM_001415146, NM_001415147, NM_001415148, NM_001415149, NM_001415150, NM_001455, NM_201559

CCDS: CCDS5068

Canonical transcript exons

ENST00000406360 — 3 exons

Exon	Start	End
ENSE00001548163	108560917	108561829
ENSE00001912084	108679827	108684774
ENSE00003656576	108663455	108664889

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.6528 / max 639.6168, expressed in 1773 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69193	7.1995	1617
69191	4.4346	1393
69195	0.7174	375
69192	0.3970	173
69194	0.3565	107
69202	0.2956	112
69198	0.2029	90
69203	0.0492	12

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.21	gold quality
trabecular bone tissue	UBERON:0002483	98.58	gold quality
cerebellar vermis	UBERON:0004720	98.23	gold quality
nipple	UBERON:0002030	98.21	gold quality
middle temporal gyrus	UBERON:0002771	98.11	gold quality
visceral pleura	UBERON:0002401	97.58	gold quality
buccal mucosa cell	CL:0002336	97.46	gold quality
tibialis anterior	UBERON:0001385	97.39	gold quality
pericardium	UBERON:0002407	97.29	gold quality
parietal pleura	UBERON:0002400	97.19	gold quality
amniotic fluid	UBERON:0000173	97.18	gold quality
pylorus	UBERON:0001166	97.13	gold quality
cardia of stomach	UBERON:0001162	97.00	gold quality
tibia	UBERON:0000979	96.87	gold quality
cartilage tissue	UBERON:0002418	96.55	gold quality
deltoid	UBERON:0001476	96.16	gold quality
pleura	UBERON:0000977	96.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.09	gold quality
epithelium of mammary gland	UBERON:0003244	96.00	gold quality
oocyte	CL:0000023	95.98	gold quality
oviduct epithelium	UBERON:0004804	95.86	gold quality
saphenous vein	UBERON:0007318	95.86	gold quality
mammary duct	UBERON:0001765	95.80	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.69	gold quality
urethra	UBERON:0000057	95.67	gold quality
renal medulla	UBERON:0000362	95.62	gold quality
cervix squamous epithelium	UBERON:0006922	95.56	gold quality
trachea	UBERON:0003126	95.50	gold quality
penis	UBERON:0000989	95.36	gold quality
skin of hip	UBERON:0001554	95.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10290	no	100.32
E-MTAB-6142	no	85.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

206 targets.

Target	Regulation
ABCB1	Activation
ABCC8
AKT1
AKT2
ANG	Repression
ANGPT2	Activation
APP	Repression
AR	Activation
ARC	Unknown
ASPM	Repression
ATM	Unknown
ATP8A1	Activation
BBC3	Unknown
BCL2L11	Unknown
BCL6	Activation
BIRC5	Unknown
BMP15	Repression
BMP4	Activation
BNIP3
BNIP3L	Activation
BTG1	Activation
CASP1	Unknown
CASP3	Unknown
CASP8	Unknown
CASP9	Unknown
CAT	Activation
CAV1
CBLB	Activation
CCN1	Unknown
CCND1	Repression

JASPAR motifs

Motif	Name	Family
MA0157.1	FOXO3	FOX
MA0157.2	FOXO3	FOX

JASPAR matrix evidence (PMIDs): PMID:17916232

Upstream regulators (CollecTRI, top): ABL1, CREB1, E2F1, FOS, FOXO1, FOXO3, FOXS1, GATA2, H4C2, JUN, MYC, NFE2L2, NFKB1, NR0B2, NR3C1, PPARGC1A, PRLR, RELA, SETD2, SIRT1, SIRT3, SMAD3, STAT1, STAT3, TEAD1, TP53, TSC22D3

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors (PMID:11884591)
• FKHRL1 role in downregulation of HMG-CoA synthase (PMID:12027802)
• TRAIL is a direct target of FKHRL1 (PMID:12351634)
• these results indicate that the proteolytic cleavage of FOXO3a by caspases may represent a novel regulatory mechanism of FOXO3a activity during death receptor signaling. (PMID:12881712)
• fMLP-stimulated neutrophils coordinate the regulation of FOXO transcription factors and the survival factor Mcl-1, a mechanism that may allow neutrophils to alter their survival. (PMID:12960271)
• up-regulation of FoxO3a by paclitaxel can result in increased levels of Bim mRNA and protein, which can be a direct cause of apoptosis in breast cancer cells (PMID:14527951)
• FOXO3a is a downstream target of Akt in endothelial cells that can promote apoptosis via FLIP down-regulation and activation of the extrinsic apoptotic pathway (PMID:14551207)
• sterol carrier protein 2 is upregulated by the daf-16-like Forkhead transcription factor FOXO3a (PMID:14563822)
• FoxO3a controls expression of BTG1 and subsequent regulation of protein arginine methyl transferase activity. (PMID:14734530)
• FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by the expression of NPM-ALK. (PMID:14962911)
• FLT3 can negatively regulate Foxo transcription factors, thereby promoting cell survival and proliferation. (PMID:14981546)
• FOXO factors are important for glucocorticoid-stimulated hPDK4 expression. (PMID:15047604)
• Results describe the regulation of FOXO3a by brain-derived neurotrophic factor (BDNF) in retinoic acid-differentiated human SH-SY5Y neuroblastoma cells. (PMID:15207915)
• MUC1 regulates the FOXO3a signaling pathway in a survival response to oxidative stress. (PMID:15322085)
• conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels (PMID:15509806)
• the activation of FKHRL1 seems to be recognized as one of the specific features of invasive ductal carcinoma of the breast. (PMID:15551757)
• Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. (PMID:15616007)
• Balloon angioplasty leads to the phosphorylation of FKHRL1 and decreased expression of p27, thereby promoting a proliferative phenotype in vascular smooth muscle (PMID:15662024)
• FOXO3a, is involved in the transcriptional activation of prosurvival and proapoptotic molecules in tumor cells. (PMID:15674333)
• conditional activation of FoxO3a leads to induction of Bim expression and apoptosis (PMID:15688014)
• FOXO3a expression and reduced p27KIP1 promoter transactivation are seen in the progression of LNCaP human prostate cancer cells to androgen independence (PMID:15798096)
• Induction of androgen receptor expression by P13K/Akt downstream substrate, FOXO3A, and their role in apoptosis of LNCAP prostate cancer cells is presented. (PMID:16061480)
• Data show that Foxo1 and Foxo3a are the most abundant Foxo isoforms in mature endothelial cells and that overexpression of constitutively active Foxo1 or Foxo3a, but not Foxo4, significantly inhibits endothelial cell migration and tube formation in vitro. (PMID:16100571)
• These studies show IGF-I phosphorylation of FKHR and FKHRL1 via a PI3-K-dependent pathway in neuroblastoma cells. (PMID:16133873)
• RUNX3 cooperates with FoxO3a/FKHRL1 to participate in the induction of apoptosis by activating Bim (PMID:16373335)
• FKHRL1 regulates the human inducible nitric-oxide synthase promoter via a specific enhancer sequence. (PMID:16687394)
• Glucocorticoid receptor-mediated FOXO3a inactivation is an important mechanism contributing to glucocorticoid-mediated mammary epithelial cell survival. (PMID:16690749)
• Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. (PMID:16709600)
• FoxM1 and FoxO3a cooperate to regulate ERalpha gene transcription (PMID:16809346)
• We conclude that Noxa and Bim establish a connection between FKHRL1 and mitochondria, and that both BH3-only proteins are critically involved in FKHRL1-induced apoptosis in neuroblastoma. (PMID:16888645)
• Potentially causal mutations in FOXO3A (2/90; 2.2%) and FOXO1A (1/90; 1.1%) were identified in POF patients. (PMID:16979636)
• FKHRL1 is associated with the apoptosis-inducing effect of endogenous nitric oxide suppression in cancer cells. (PMID:17044646)
• We conclude that knockdown of WTp66ShcA redox function prevents HG-dependent FOXO3a regulation and promotes the survival phenotype. (PMID:17077388)
• the survival of CD4+ central memory T cells depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a) (PMID:17190839)
• rhFOXO3a is a negative transcription factor of CYR61 in rat VSMC. Suppression of CYR61 is among several mechanisms by which FOXO3a inhibits VSMC proliferation and neointimal hyperplasia. (PMID:17234971)
• ZNF198-FGFR1 activated prosurvival signaling pathways, resulting in elevated phosphorylation of FOXO3a. The phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis (PMID:17389761)
• These results provide evidence of direct regulation of Mxi1 by FOXO3a and imply an additional mechanism through which the PI3-kinase/Akt/FOXO pathway can modulate Myc function. (PMID:17452451)
• A critical role of FOXO3a is demonstrated in both spontaneous and homeostatic chemokine-induced survival of chronic lymphocytic leukemia B-cells. (PMID:17496928)
• 3,3’-diindolylmethane -induced cell growth inhibition and apoptosis induction are partly mediated through the regulation of Akt/FOXO3a/GSK-3beta/beta-catenin/AR signaling (PMID:17522055)
• Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3 (PMID:17558024)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Foxo3	ENSMUSG00000048756
rattus_norvegicus	Foxo3	ENSRNOG00000000299

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein O3 — O43524 (reviewed: O43524)

Alternative names: AF6q21 protein, Forkhead in rhabdomyosarcoma-like 1

All UniProt accessions (2): O43524, A0A856PRE8

UniProt curated annotations — full annotation on UniProt →

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. 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. Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. 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. In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. 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. Also acts as a key regulator of regulatory T-cells (Treg) differentiation by activating expression of FOXP3.

Subunit / interactions. 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. Also forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT. Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity. 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. Interacts (deacetylated form) with SKP2. Interacts with CHUK and IKBKB. Interacts with CAMK2A, CAMK2B and calcineurin A. Interacts with NUPR1; this interaction represses FOXO3 transactivation. Interacts with CTDSPL2.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Mitochondrion matrix. Mitochondrion outer membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. In the presence of survival factors such as IGF1, 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. In response to metabolic stress, phosphorylated by AMPK on Ser-30 which mediates FOXO3 mitochondrial translocation. 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. Phosphorylated by CHUK/IKKA and IKBKB/IKKB. 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. May be dephosphorylated by calcineurin A on Ser-299 which abolishes FOXO3 transcriptional activity. In cancer cells, ERK mediated-phosphorylation of Ser-12 is required for mitochondrial translocation of FOXO3 in response to metabolic stress or chemotherapeutic agents. Phosphorylation at Ser-253 promotes its degradation by the proteasome. Dephosphorylation at Ser-253 by protein phosphatase 2A (PPP2CA) promotes its stabilization; interaction with PPP2CA is enhanced by AMBRA1. Dephosphorylated at Ser-253 by CTDSPL2. Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation. Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress. Deacetylated by SIRT3. Deacetylation by SIRT3 stimulates FOXO3-mediated mtDNA transcriptional activity in response to metabolic stress. 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. Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation. The N-terminus is cleaved following import into the mitochondrion.

Disease relevance. A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with KMT2A/MLL1.

Isoforms (2)

UniProt ID	Names	Canonical?
O43524-1	1	yes
O43524-2	2

RefSeq proteins (12): NP_001402068, NP_001402069, NP_001402071, NP_001402073, NP_001402074, NP_001402075, NP_001402076, NP_001402077, NP_001402078, NP_001402079, NP_001446, NP_963853 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR032067	FOXO-TAD	Domain
IPR032068	FOXO_KIX-bd	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00250, PF16675, PF16676

UniProt features (89 total): modified residue 28, mutagenesis site 26, sequence conflict 9, strand 6, compositionally biased region 5, region of interest 5, helix 4, turn 2, chain 1, DNA-binding region 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9QNG	X-RAY DIFFRACTION	1.35
7V9B	X-RAY DIFFRACTION	1.85
2UZK	X-RAY DIFFRACTION	2.7
2K86	SOLUTION NMR
2LQH	SOLUTION NMR
2LQI	SOLUTION NMR
6MNL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43524-F1	51.60	0.11

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (28): 30, 32, 46, 149, 179, 209, 215, 230, 242, 253, 262, 271, 280, 284, 290, 294, 299, 311, 315, 399 …

Mutagenesis-validated functional residues (26):

Position	Phenotype
2–148	loss of localization to the mitochondrion outer membrane and loss of translocation into the mitochondrion following meta
2–30	loss of translocation into the mitochondrion following metabolic stress.
12	in normal cells, no defect in mitochondrion import following metabolic stress. in cancer cells, defective mitochondrion
30	abolishes phosphorylation. loss of localization to the mitochondrion outer membrane and loss of translocation into the m
32	abolishes ywhaz-binding; when associated with a-253. exclusively nuclear, induces transcription and promotes apoptosis;
80–108	loss of translocation into the mitochondrion following metabolic stress.
179	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-399; a-4
209	impairs nuclear translocation upon oxidative stress.
242–271	loss of nuclear import.
242	slightly decreases dna affinity.
242	reduces acetylation, increases interaction with skp2 and inhibits foxo3 ubiquitination and degradation; when associated
245	decreases dna affinity.
253	abolishes ywhaz-binding; when associated with a-32. exclusively nuclear, induces transcription and promotes apoptosis; w
259	reduces acetylation, increases interaction with skp2 and inhibits foxo3 ubiquitination and degradation; when associated
269	methylation levels similar to wild-type; when associated with arg-270.
270	methylation levels similar to wild-type; when associated with arg-269.
271	methylation levels strongly reduced.
290	reduces acetylation, increases interaction with skp2 and inhibits foxo3 ubiquitination and degradation; when associated
315	no effect on ywhaz-binding. promotes nuclear translocation. exclusively nuclear, induces transcription and promotes apop
399	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-179; a-4
413	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-179; a-3
555	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-179; a-3
569	reduces acetylation, increases interaction with skp2 and inhibits foxo3 ubiquitination and degradation; when associated
588	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-179; a-3
626	decreased phosphorylation by ampk and impaired ability to transactivate a reporter gene; when associated with a-179; a-3

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-198693	AKT phosphorylates targets in the nucleus
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8862803	Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models
R-HSA-8952158	RUNX3 regulates BCL2L11 (BIM) transcription
R-HSA-9607240	FLT3 Signaling
R-HSA-9614399	Regulation of localization of FOXO transcription factors
R-HSA-9614657	FOXO-mediated transcription of cell death genes
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9617629	Regulation of FOXO transcriptional activity by acetylation
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)

MSigDB gene sets: 692 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, BIOCARTA_PTEN_PATHWAY, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GU_PDEF_TARGETS_DN, GCM_GSPT1, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (47): negative regulation of transcription by RNA polymerase II (GO:0000122), ovulation from ovarian follicle (GO:0001542), initiation of primordial ovarian follicle growth (GO:0001544), antral ovarian follicle growth (GO:0001547), oocyte maturation (GO:0001556), regulation of transcription by RNA polymerase II (GO:0006357), mitochondrial transcription (GO:0006390), regulation of translation (GO:0006417), response to xenobiotic stimulus (GO:0009410), positive regulation of autophagy (GO:0010508), positive regulation of muscle atrophy (GO:0014737), DNA damage response, signal transduction by p53 class mediator (GO:0030330), negative regulation of cell migration (GO:0030336), tumor necrosis factor-mediated signaling pathway (GO:0033209), cellular response to oxidative stress (GO:0034599), cellular response to glucose starvation (GO:0042149), response to starvation (GO:0042594), positive regulation of apoptotic process (GO:0043065), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of regulatory T cell differentiation (GO:0045591), positive regulation of erythrocyte differentiation (GO:0045648), negative regulation of neuron differentiation (GO:0045665), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), brain morphogenesis (GO:0048854), canonical Wnt signaling pathway (GO:0060070), response to fatty acid (GO:0070542), cellular response to glucose stimulus (GO:0071333), cellular response to corticosterone stimulus (GO:0071386), cellular response to hypoxia (GO:0071456), response to dexamethasone (GO:0071548), negative regulation of canonical Wnt signaling pathway (GO:0090090), neuronal stem cell population maintenance (GO:0097150), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), positive regulation of hydrogen peroxide-mediated programmed cell death (GO:1901300), positive regulation of miRNA transcription (GO:1902895), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), cellular response to amyloid-beta (GO:1904646), cellular response to nerve growth factor stimulus (GO:1990090), response to water-immersion restraint stress (GO:1990785)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coregulator binding (GO:0001221), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), protein kinase binding (GO:0019901), chromatin DNA binding (GO:0031490), mitochondrial transcription factor activity (GO:0034246), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (11): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), protein-containing complex (GO:0032991), RNA polymerase II transcription repressor complex (GO:0090571), mitochondrion (GO:0005739), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
FOXO-mediated transcription	5
Developmental Biology	1
PIP3 activates AKT signaling	1
PI3K/AKT Signaling in Cancer	1
MAPK family signaling cascades	1
Signaling by Interleukins	1
Neurodegenerative Diseases	1
Transcriptional regulation by RUNX3	1
Cytokine Signaling in Immune system	1
Extra-nuclear estrogen signaling	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
ovulation cycle process	3
mitochondrion	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
ovarian follicle development	2
developmental process involved in reproduction	2
regulation of DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription regulator activity	2
DNA binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
female gonad development	1
ovulation	1
developmental growth	1
cell maturation	1
oocyte development	1
mitochondrial RNA metabolic process	1
DNA-templated transcription	1
mitochondrial gene expression	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
response to chemical	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of muscle atrophy	1
positive regulation of muscle adaptation	1
muscle atrophy	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1

Protein interactions and networks

STRING

4624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXO3	CDK2	P24941	995
FOXO3	E2F1	Q01094	995
FOXO3	HIF1A	Q16665	995
FOXO3	CTNNB1	P35222	994
FOXO3	CDKN1A	P38936	994
FOXO3	TP53	P04637	992
FOXO3	PTK2	Q05397	992
FOXO3	ID1	P41134	989
FOXO3	MDM2	Q00987	983
FOXO3	PPARGC1A	Q9UBK2	979
FOXO3	SIRT1	Q96EB6	964
FOXO3	NRF1	Q16656	933
FOXO3	SIRT3	Q9NTG7	930
FOXO3	AKT1	P31749	929
FOXO3	SMAD2	Q15796	926

IntAct

168 interactions, top by confidence:

A	B	Type	Score
FOXO3	YWHAZ	psi-mi:“MI:0915”(physical association)	0.850
SMAD4	FOXO3	psi-mi:“MI:0915”(physical association)	0.800
FOXO3	SMAD4	psi-mi:“MI:0915”(physical association)	0.800
FOXO3	SMAD4	psi-mi:“MI:0407”(direct interaction)	0.800
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
SMAD4	FOXO3	psi-mi:“MI:0914”(association)	0.800
SMAD4	FOXO3	psi-mi:“MI:2364”(proximity)	0.800
YWHAB	WDR62	psi-mi:“MI:0914”(association)	0.770
AKT1	FOXO3	psi-mi:“MI:0915”(physical association)	0.750
FOXO3	AKT1	psi-mi:“MI:2364”(proximity)	0.750
AKT1	FOXO3	psi-mi:“MI:2364”(proximity)	0.750
AKT1	FOXO3	psi-mi:“MI:0217”(phosphorylation reaction)	0.750
SIRT1	FOXO3	psi-mi:“MI:0915”(physical association)	0.700
FOXO3	SIRT1	psi-mi:“MI:0915”(physical association)	0.700
SIRT1	FOXO3	psi-mi:“MI:0407”(direct interaction)	0.700
FOXO3	YWHAE	psi-mi:“MI:0915”(physical association)	0.690
FOXO3	SMAD3	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (197): FOXO3 (Affinity Capture-Western), FOXO3 (Affinity Capture-Western), Ep300 (Reconstituted Complex), FOXO3 (Proximity Label-MS), FOXO3 (Affinity Capture-MS), FOXO3 (Co-localization), FOXO3 (Co-localization), FOXO3 (Co-localization), PPP2CB (Affinity Capture-MS), PLK1 (Affinity Capture-MS), PPP2R4 (Affinity Capture-MS), PPP2R1A (Affinity Capture-MS), PPP2R1B (Affinity Capture-MS), USP7 (Affinity Capture-MS), PLK1 (Affinity Capture-Western)

ESM2 similar proteins: A0A0R4IBL7, A2A891, A3RK74, A4L7N3, B5DE09, E1BPQ1, G3V7R4, O15014, O43524, P11420, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P70365, P98180, Q01978, Q12778, Q14135, Q15596, Q15788, Q4PJW2, Q53TQ3, Q60420, Q60722, Q61026, Q61286, Q62655, Q66IY8, Q66JJ0, Q6DIH5, Q6EUW2, Q6NZT6, Q6PCG7, Q7T2G1, Q7ZXS3, Q80V24

Diamond homologs: A0A2Z4LIS9, A3RK74, A3RK75, A4L7N3, A8MYZ6, B3LYS5, B3P0K6, B4G4S8, B4HF64, B4JSC2, B4KBF6, B4MB78, B4NFR1, B4PTD3, E1BPQ1, G3V7R4, O16850, O43524, P0CG31, P23512, P32182, P32183, P32315, P33205, P33206, P35582, P35583, P35584, P55317, P55318, P84961, P98177, Q07342, Q10924, Q12778, Q28EM1, Q298W7, Q3Y598, Q4VUF1, Q63248

SIGNOR signaling

138 interactions.

A	Effect	B	Mechanism
DYRK1A	“down-regulates activity”	FOXO3	phosphorylation
SIRT1	“up-regulates activity”	FOXO3	deacetylation
SIRT1	“down-regulates activity”	FOXO3	deacetylation
CHUK	down-regulates	FOXO3	phosphorylation
IKBKB	down-regulates	FOXO3	phosphorylation
14-3-3	down-regulates	FOXO3	binding
FOXO3	“up-regulates quantity by expression”	CITED2	“transcriptional regulation”
SETD2	“up-regulates quantity by expression”	FOXO3	“transcriptional regulation”
MAPK1	“down-regulates quantity by destabilization”	FOXO3	phosphorylation
CSNK1A1	down-regulates	FOXO3	phosphorylation
PPP2CA	up-regulates	FOXO3	dephosphorylation
PPP2CA	“up-regulates activity”	FOXO3	dephosphorylation
TEAD1	“up-regulates quantity by expression”	FOXO3	“transcriptional regulation”
AKT1	“down-regulates activity”	FOXO3	phosphorylation
MAPK14	up-regulates	FOXO3	phosphorylation
STK4	up-regulates	FOXO3	phosphorylation
PIM1	down-regulates	FOXO3	phosphorylation
PIM1	“down-regulates activity”	FOXO3	phosphorylation
FOXO3	“up-regulates quantity by expression”	MYOD1	“transcriptional regulation”
AKT	“down-regulates activity”	FOXO3	phosphorylation
AKT3	down-regulates	FOXO3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 71 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	8	106.8×	3e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	9	106.1×	8e-15
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	82.5×	9e-11
Activation of BH3-only proteins	8	69.7×	1e-11
FOXO-mediated transcription	11	64.8×	3e-15
RHO GTPases activate PKNs	8	44.5×	5e-10
Intrinsic Pathway for Apoptosis	8	41.1×	8e-10
SARS-CoV-1-host interactions	9	27.7×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	29.5×	8e-05
positive regulation of miRNA transcription	6	28.1×	2e-05
negative regulation of osteoblast differentiation	5	23.8×	2e-04
regulation of mitotic cell cycle	6	23.3×	3e-05
epidermal growth factor receptor signaling pathway	5	20.0×	3e-04
intracellular protein localization	9	15.2×	2e-06
MAPK cascade	6	14.8×	2e-04
transforming growth factor beta receptor signaling pathway	5	12.8×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — AML, MBL.

Clinical variants and AI predictions

ClinVar

102 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	6
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1993 predictions. Top by Δscore:

Variant	Effect	Δscore
6:108662150:G:GT	donor_gain	1.0000
6:108663453:A:AG	acceptor_gain	1.0000
6:108663454:G:GA	acceptor_gain	1.0000
6:108663454:GA:G	acceptor_gain	1.0000
6:108663454:GAACT:G	acceptor_gain	1.0000
6:108560004:G:T	donor_gain	0.9900
6:108560008:G:GT	donor_gain	0.9900
6:108561072:T:A	acceptor_gain	0.9900
6:108561828:AGGT:A	donor_loss	0.9900
6:108561830:G:GC	donor_loss	0.9900
6:108561831:T:G	donor_loss	0.9900
6:108566218:C:G	donor_gain	0.9900
6:108663450:TGCA:T	acceptor_loss	0.9900
6:108663451:GCAG:G	acceptor_loss	0.9900
6:108663452:CA:C	acceptor_loss	0.9900
6:108663454:GAA:G	acceptor_gain	0.9900
6:108663454:GAAC:G	acceptor_gain	0.9900
6:108677110:G:GA	donor_gain	0.9900
6:108560011:GCGAG:G	donor_gain	0.9800
6:108560012:CGAGG:C	donor_loss	0.9800
6:108560013:GAGG:G	donor_loss	0.9800
6:108560014:AG:A	donor_loss	0.9800
6:108560015:GGTAG:G	donor_loss	0.9800
6:108560016:GT:G	donor_loss	0.9800
6:108560017:T:G	donor_loss	0.9800
6:108561794:GA:G	donor_gain	0.9800
6:108639092:A:T	donor_gain	0.9800
6:108663450:T:TA	acceptor_gain	0.9800
6:108664720:T:TA	donor_gain	0.9800
6:108664721:A:AA	donor_gain	0.9800

AlphaMissense

4411 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:108561305:T:A	W33R	1.000
6:108561305:T:C	W33R	1.000
6:108561307:G:C	W33C	1.000
6:108561307:G:T	W33C	1.000
6:108561671:A:G	N155D	1.000
6:108561673:C:A	N155K	1.000
6:108561673:C:G	N155K	1.000
6:108561677:T:A	W157R	1.000
6:108561677:T:C	W157R	1.000
6:108561678:G:C	W157S	1.000
6:108561679:G:C	W157C	1.000
6:108561679:G:T	W157C	1.000
6:108561680:G:A	G158R	1.000
6:108561680:G:C	G158R	1.000
6:108561681:G:A	G158E	1.000
6:108561681:G:C	G158A	1.000
6:108561681:G:T	G158V	1.000
6:108561690:C:A	S161Y	1.000
6:108561690:C:T	S161F	1.000
6:108561692:T:C	Y162H	1.000
6:108561693:A:G	Y162C	1.000
6:108561702:T:A	L165Q	1.000
6:108561702:T:C	L165P	1.000
6:108561705:T:A	I166N	1.000
6:108561705:T:C	I166T	1.000
6:108561705:T:G	I166S	1.000
6:108561713:G:C	A169P	1.000
6:108561714:C:A	A169D	1.000
6:108561717:T:A	I170N	1.000
6:108561717:T:G	I170S	1.000

dbSNP variants (sampled 300 via entrez): RS1000004149 (6:108660596 G>T), RS1000006692 (6:108616153 A>G), RS1000039915 (6:108572053 A>T), RS1000077832 (6:108560322 C>T), RS1000087781 (6:108603216 G>A,T), RS1000122650 (6:108623711 C>G,T), RS1000202040 (6:108590742 A>G), RS1000253297 (6:108565542 T>A), RS1000257288 (6:108597867 C>T), RS1000258407 (6:108666601 C>T), RS1000267656 (6:108558069 T>A,C,G), RS1000278878 (6:108631318 C>G), RS1000295647 (6:108578425 A>G), RS1000300576 (6:108656995 T>C), RS1000303653 (6:108641890 A>G)

Disease associations

OMIM: gene MIM:602681 | disease phenotypes: MIM:155255

GenCC curated gene-disease

Mondo (2): choroid plexus carcinoma (MONDO:0016718), medulloblastoma (MONDO:0007959)

Orphanet (2): Choroid plexus carcinoma (Orphanet:251899), Medulloblastoma (Orphanet:616)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

66 associations (top):

Study	Trait	p-value
GCST000268_3	Normalized brain volume	7.000000e-06
GCST000937_2	Insulin-like growth factors	5.000000e-07
GCST001942_10	Prostate cancer	8.000000e-09
GCST002783_242	Body mass index	7.000000e-08
GCST002783_421	Body mass index	2.000000e-08
GCST002783_470	Body mass index	1.000000e-07
GCST002935_3	Lead levels	3.000000e-07
GCST004053_2	Poor prognosis in Crohn’s disease	1.000000e-08
GCST004065_2	Waist circumference	2.000000e-11
GCST004065_5	Waist circumference	3.000000e-06
GCST004065_60	Waist circumference	6.000000e-08
GCST004066_88	Hip circumference	3.000000e-08
GCST004364_1	Intelligence	2.000000e-12
GCST004364_19	Intelligence	1.000000e-13
GCST004495_42	BMI (adjusted for smoking behaviour)	2.000000e-06
GCST004557_58	Body mass index	3.000000e-08
GCST004557_94	Body mass index	1.000000e-06
GCST004558_217	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-06
GCST004558_242	Body mass index (joint analysis main effects and physical activity interaction)	6.000000e-08
GCST004559_127	Body mass index in physically active individuals	2.000000e-06
GCST004559_170	Body mass index in physically active individuals	7.000000e-07
GCST004611_62	High light scatter reticulocyte count	3.000000e-10
GCST004612_23	High light scatter reticulocyte percentage of red cells	1.000000e-11
GCST004616_24	Platelet distribution width	4.000000e-09
GCST004619_53	Reticulocyte fraction of red cells	2.000000e-09
GCST004904_261	Body mass index	4.000000e-13
GCST004946_140	Schizophrenia	2.000000e-11
GCST005316_38	Intelligence (MTAG)	8.000000e-15
GCST005316_39	Intelligence (MTAG)	1.000000e-10
GCST005316_42	Intelligence (MTAG)	6.000000e-09

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004627	IGF-1 measurement
EFO:0004340	body mass index
EFO:0007936	disease prognosis measurement
EFO:0004337	intelligence
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0007986	reticulocyte count
EFO:0007984	platelet component distribution width
EFO:0008393	reaction time measurement
EFO:0005763	pulse pressure measurement
EFO:0009863	anxiety measurement
EFO:0004338	body weight
EFO:0004784	self reported educational attainment
EFO:0004346	neuroimaging measurement
EFO:0007796	parental longevity
EFO:0009762	healthspan
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0006935	thalamus volume
EFO:0004980	appendicular lean mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
C562943	Choroid Plexus Carcinoma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5778 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17069665	FOXO3		0.00	0
rs4946936	FOXO3		0.00	0

CTD chemical–gene interactions

179 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases localization, increases reaction, affects binding, affects reaction, decreases expression (+9 more)	13
Doxorubicin	affects reaction, decreases reaction, increases response to substance, affects localization, decreases expression (+3 more)	6
Cadmium Chloride	increases phosphorylation, increases abundance, affects reaction, decreases response to substance, decreases reaction (+2 more)	6
Wortmannin	increases phosphorylation, decreases activity, increases expression, decreases phosphorylation, decreases reaction	5
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression, increases localization, decreases reaction (+3 more)	5
Valproic Acid	decreases expression, increases methylation	5
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects localization, increases activity, decreases reaction, increases phosphorylation, decreases phosphorylation	4
Cisplatin	increases expression, decreases expression, increases localization, affects cotreatment, decreases reaction (+5 more)	4
Estradiol	increases phosphorylation, decreases expression, decreases phosphorylation, increases expression, affects reaction (+2 more)	4
Hydrogen Peroxide	affects reaction, increases expression, decreases reaction, affects cotreatment, increases reaction (+3 more)	4
sodium arsenite	affects expression, affects cotreatment, affects phosphorylation, increases expression, decreases expression	3
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, decreases phosphorylation, increases response to substance	3
Benzo(a)pyrene	decreases reaction, increases phosphorylation, decreases methylation, affects localization, increases reaction	3
Niacinamide	affects cotreatment, increases acetylation, increases expression, decreases reaction, increases reaction	3
Quercetin	decreases reaction, increases expression, decreases expression, decreases phosphorylation	3
bisphenol A	decreases expression, affects cotreatment, increases expression	2
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases phosphorylation, decreases phosphorylation, decreases reaction	2
arsenite	increases phosphorylation, affects binding, decreases reaction	2
RTKI cpd	affects localization, decreases reaction, decreases activity, increases phosphorylation	2
pyrazolanthrone	decreases phosphorylation, decreases reaction, increases phosphorylation, affects localization	2
tomentosin	decreases reaction, increases expression, affects reaction	2
NVP-BKM120	affects cotreatment, increases expression, increases cleavage, increases reaction	2
Fulvestrant	affects localization, decreases reaction, increases expression, affects reaction	2
Acetaminophen	increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Ethanol	affects cotreatment, increases reaction, increases phosphorylation, increases expression, increases response to substance (+3 more)	2
Dichlorodiphenyl Dichloroethylene	decreases expression, increases activity	2
Etoposide	increases response to substance, increases phosphorylation, decreases expression, decreases reaction	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	decreases phosphorylation, decreases reaction, increases phosphorylation, increases reaction	2

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3372933	Binding	Induction of FOXO3a binding to SIRT1 in HUVEC at 50 uM after 24 hrs by chromatin immunoprecipitation assay	Enantioselective induction of SIRT1 gene by syringaresinol from Panax ginseng berry and Acanthopanax senticosus Harms stem. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 7 cancer cell line, 3 embryonic stem cell, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2C7	SEES3-1V human FOXO3, clone1	Embryonic stem cell	Male
CVCL_A2C8	SEES3-1V human FOXO3, clone2	Embryonic stem cell	Male
CVCL_A2C9	SEES3-1V human FOXO3, clone3	Embryonic stem cell	Male
CVCL_B1AV	Abcam HEK293 FOXO3 KO	Transformed cell line	Female
CVCL_B2X9	Abcam HEK293T FOXO3 KO	Transformed cell line	Female
CVCL_B7XC	Abcam Raji FOXO3 KO	Cancer cell line	Male
CVCL_B9Y1	Abcam THP-1 FOXO3 KO	Cancer cell line	Male
CVCL_C6ZV	Abcam PC-3 FOXO3 KO	Cancer cell line	Male
CVCL_E0D9	Ubigene HeLa FOXO3 KO	Cancer cell line	Female
CVCL_F1QJ	HyCyte HK-2 KO-hFOXO3	Transformed cell line	Male

Clinical trials (associated diseases)

147 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT00085735	PHASE3	COMPLETED	Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma
NCT00336024	PHASE3	COMPLETED	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
NCT00392327	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
NCT01351870	PHASE3	COMPLETED	Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)
NCT07291102	PHASE3	NOT_YET_RECRUITING	Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma
NCT00031590	PHASE2	TERMINATED	Low-Dose Radiation and Combination Chemotherapy Following Surgery in Children With Newly Diagnosed Medulloblastoma
NCT00180791	PHASE2	UNKNOWN	High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood
NCT00180947	PHASE2	UNKNOWN	Study of Vinorelbine and Cyclofosfamide Among Patients With Refractory Tumours or in Relapse
NCT00404495	PHASE2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00407433	PHASE2	COMPLETED	Clinical Studies of Gemcitabine-Oxaliplatin
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00601003	PHASE2	COMPLETED	Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01217437	PHASE2	COMPLETED	Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors
NCT01326104	PHASE2	COMPLETED	Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01542736	PHASE2	COMPLETED	Concurrent Carboplatin and Reduced Dose Craniospinal Radiation for Medulloblastoma and Primitive Neuroectodermal Tumor (PNET)
NCT01708174	PHASE2	COMPLETED	A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
NCT01857453	PHASE2	UNKNOWN	Interest of a Dose Decrease for Radiotherapy Associated With Chemotherapy for Treatment of Standard Risk Adult Medulloblastomas
NCT01878617	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
NCT02017964	PHASE2	COMPLETED	Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed, Non-metastatic Desmoplastic Medulloblastoma
NCT02441062	PHASE2	COMPLETED	Impact of Ga-68 DOTATOC PET-CT Imaging in Management of Neuroendocrine Tumors
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02681705	PHASE2	UNKNOWN	Radiation Therapy and Combination Chemotherapy for Medulloblastoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT02724579	PHASE2	ACTIVE_NOT_RECRUITING	Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
NCT03013387	PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 90Y-DOTATOC
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03257631	PHASE2	COMPLETED	A Study of Pomalidomide Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors
NCT03273712	PHASE2	COMPLETED	Dosimetry-Guided, Peptide Receptor Radiotherapy (PRRT) With 90Y-DOTA- tyr3-Octreotide (90Y-DOTATOC)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)