FOXO1

Summary

FOXO1 (forkhead box O1, HGNC:3819) is a protein-coding gene on chromosome 13q14.11, encoding Forkhead box protein O1 (Q12778). Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress.

This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. Translocation of this gene with PAX3 has been associated with alveolar rhabdomyosarcoma.

Source: NCBI Gene 2308 — RefSeq curated summary.

At a glance

• GWAS associations: 46
• Clinical variants (ClinVar): 96 total — 1 pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• Transcription factor: yes — 289 downstream targets (CollecTRI)
• MANE Select transcript: NM_002015

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3819
Approved symbol	FOXO1
Name	forkhead box O1
Location	13q14.11
Locus type	gene with protein product
Status	Approved
Aliases	FKH1
Ensembl gene	ENSG00000150907
Ensembl biotype	protein_coding
OMIM	136533
Entrez	2308

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000379561, ENST00000473775, ENST00000655267, ENST00000660760, ENST00000909775, ENST00000962362

RefSeq mRNA: 1 — MANE Select: NM_002015 NM_002015

CCDS: CCDS9371

Canonical transcript exons

ENST00000379561 — 3 exons

Exon	Start	End
ENSE00001094288	40559509	40560860
ENSE00001481591	40555667	40559034
ENSE00001481602	40665583	40666641

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.7749 / max 570.3053, expressed in 1727 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136917	20.8314	1678
136916	12.7935	1534
136915	0.1499	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	97.92	gold quality
synovial joint	UBERON:0002217	96.58	gold quality
layer of synovial tissue	UBERON:0007616	95.23	gold quality
pericardium	UBERON:0002407	94.89	gold quality
middle frontal gyrus	UBERON:0002702	94.81	gold quality
left ovary	UBERON:0002119	94.70	gold quality
ovary	UBERON:0000992	94.33	gold quality
right ovary	UBERON:0002118	94.23	gold quality
tendon of biceps brachii	UBERON:0008188	94.18	gold quality
tendon	UBERON:0000043	94.13	gold quality
calcaneal tendon	UBERON:0003701	93.93	gold quality
myometrium	UBERON:0001296	93.87	gold quality
sural nerve	UBERON:0015488	93.86	gold quality
gastrocnemius	UBERON:0001388	93.67	gold quality
superficial temporal artery	UBERON:0001614	93.58	gold quality
lower lobe of lung	UBERON:0008949	93.26	gold quality
tibial nerve	UBERON:0001323	93.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.11	gold quality
dorsal root ganglion	UBERON:0000044	93.10	gold quality
saphenous vein	UBERON:0007318	93.09	gold quality
trigeminal ganglion	UBERON:0001675	93.08	gold quality
nipple	UBERON:0002030	92.98	gold quality
germinal epithelium of ovary	UBERON:0001304	92.93	gold quality
adrenal tissue	UBERON:0018303	92.63	gold quality
muscle of leg	UBERON:0001383	92.54	gold quality
epithelium of nasopharynx	UBERON:0001951	92.49	gold quality
endometrium	UBERON:0001295	92.48	gold quality
uterus	UBERON:0000995	92.33	gold quality
cervix squamous epithelium	UBERON:0006922	92.17	gold quality
body of uterus	UBERON:0009853	92.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	33.70
E-ANND-3	yes	18.36
E-HCAD-25	yes	4.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

289 targets.

Target	Regulation
ABCB1	Activation
ABCC2	Unknown
ABCC9	Activation
ACACA	Activation
ACADSB	Activation
ACAT2	Repression
ACSL5	Repression
ADAM2
ADIPOQ	Activation
ADIPOR1	Activation
ADIPOR2	Unknown
ADM	Activation
ADRB3	Repression
AGRP	Activation
AICDA
ALPI	Unknown
ALPP	Activation
ANG	Repression
ANGPT2	Unknown
ANGPTL2	Unknown
APOC3	Unknown
AR	Repression
ASPM	Repression
ATP8A1	Activation
B4GALT3	Repression
BAX	Activation
BCL2	Repression
BCL2A1	Activation
BCL2L1	Repression
BCL2L11	Activation

JASPAR motifs

Motif	Name	Family
MA1947.1	ETV5::FOXO1	Ets-related::FOX
MA1947.2	ETV5::FOXO1	Ets-related::FOX
MA1953.1	FOXO1::ELF1	FOX::Ets-related
MA1953.2	FOXO1::ELF1	FOX::Ets-related
MA1954.1	FOXO1::ELK1	FOX::Ets-related
MA1954.2	FOXO1::ELK1	FOX::Ets-related
MA1955.1	FOXO1::ELK3	FOX::Ets-related
MA1955.2	FOXO1::ELK3	FOX::Ets-related
MA1956.1	FOXO1::FLI1	FOX::Ets-related
MA1956.2	FOXO1::FLI1	FOX::Ets-related

JASPAR matrix evidence (PMIDs): PMID:31913281

Upstream regulators (CollecTRI, top): E2F1, E2F2, E2F3, EBF1, ESR1, FOXA2, FOXC1, FOXO1, FOXO3, KLF5, NR1H3, NR1I3, NR3C1, PARP1, PPARD, STAT3, TBXT, TCF3, TP53, TSC22D3

miRNA regulators (miRDB)

233 targeting FOXO1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4803	99.98	71.99	3117

Literature-anchored findings (GeneRIF, showing 40)

• fuses with pax3 protein and affects the transcriptional regulation of IGF-I receptor (PMID:11735247)
• cooperation with C-EBP beta in differentiating human endometrial stromal cells (PMID:11893744)
• PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma. (PMID:12039929)
• Transcriptional repression of D-type cyclins (in Class III transcripts)is required for FKHR mediated inhibition of cell cycle progression and transformation. (PMID:12150827)
• Pax3-FKHR allele causes lethal developmental defects in knock-in mice but might be insufficient to cause muscle tumors (PMID:12242297)
• a new mechanism for androgen-mediated prostate cancer cell survival and establish FKHR as nuclear target for both AKT-dependent and -independent survival signals in prostate cancer cells. (PMID:12482965)
• FKHR and HOXA10 interact directly and can function cooperatively to stimulate IGFBP-1 promoter activity in endometrial cells (PMID:12493691)
• Hepatocyte nuclear factor-4 is a novel downstream target of insulin via this protein, which acts a a signal-regulated transcriptional inhibitor. (PMID:12519792)
• results identify a novel signaling pathway linking estrogen action to Pak1 signaling, and Pak1 to FKHR, suggesting that Pak1 is an important mediator of estrogen’s cell survival functions (PMID:12560069)
• results indicate that signaling via protein kinase B to forkhead transcription factor FKHR can account for the effect of insulin to regulate peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity via the insulin response sequence (PMID:12606503)
• Constitutive phosphorylation of FKHR transcription factor is associated with acute myeloid leukemia (PMID:12921955)
• 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)
• Analysis of amino acids that contribute to the nuclear/cytoplasmic shuttling of FOXO1 protein. (PMID:14664696)
• androgens induce increased activity of an acidic cysteine protease, which in turn cleaves FKHR, a mechanism by which androgens protect prostate cancer cells from the killing effect of FKHR. (PMID:14726521)
• FOXO factors are important for glucocorticoid-stimulated hPDK4 expression (PMID:15047604)
• FOX01 induces atrophy-related uibiquiitin ligase and causes akeletal muscle atrophy. (PMID:15109499)
• A fusion of FOXO1A and PAX3 proteins was used in the diagnosis of a solid alveolar rhabdomyosarcoma. (PMID:15140004)
• in the RD embryonal rhabdomyosarcoma cell line, PAX3-FKHR upregulates expression of the gene encoding the chemokine receptor CXCR4 (PMID:15184910)
• data suggest that phosphorylation-dependent degradation of FoxO1 by means of proteasomes plays a role in oncogenic transformation by P3k and Akt (PMID:15342912)
• Chromatin immunoprecipitation results demonstrate in vivo the association of human FOXO1 with the cyclin D2 promoter in untreated rat granulossa cells and release of FOXO1 from the cyclin D2 promoter upon addition of FSH plus activin. (PMID:15613482)
• TNF induces activation of the FOXO1 transcription factor, which acts as a master switch to control apoptosis (PMID:15632117)
• Pax3/FKHR regulates a distinct but overlapping set of genes relative to Pax3 in tumor cells and the global set of Pax3 and Pax3/FKHR gene targets is cell-type specific. (PMID:15688035)
• PAX3, PAX7 and their fusions with FKHR are each expressed in rhabdomyosarcoma tumors as a consistent mixture of functionally distinct isoforms (PMID:15688409)
• FHL2 inhibits FOXO1 activity in prostate cancer cells by promoting the deacetylation of FOXO1 by SIRT1 (PMID:15692560)
• persistent activation of PI3K results in Akt-dependent sequestration of FoxO1 outside the nucleus of T cells interacting with APCs; this compartmentalization process can affect T cell growth after Ag recognition (PMID:15778376)
• The carboxyl-terminal region lysines of Foxo1 is acetylated by p300 and stimulates Foxo1-induced transcription of IGF-binding protein-1. (PMID:15890677)
• FOXO1A regulation of the IGFBP1 expression is cell type-dependent (PMID:15987820)
• Acetylation, catalyzed by CREB-binding protein, regulates the function of Foxo1 through altering the affinity with the target DNA and the sensitivity for phosphorylation. (PMID:16076959)
• 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)
• Differentiating HESCs become dependent on progesterone signaling for survival through induction and reversible inactivation of FOXO1 suggesting a novel mechanism that links decidualization of the endometrium to menstruation (PMID:16123151)
• These studies show IGF-I phosphorylation of FKHR and FKHRL1 via a PI3-K-dependent pathway in neuroblastoma cells. (PMID:16133873)
• Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway (PMID:16282329)
• The mutant FoxO1 transgene prevents pancreatic beta cell replication in 2 mouse models of beta cell hyperplasia (PMID:16485043)
• FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver (PMID:16492665)
• FOXO1A variation is rare and is unlikely to contribute to type 2 diabetes in either Caucasian or African-American populations (PMID:16497530)
• C5b-9 regulation of the cell cycle activation in aortic endothelial cells through Akt pathway is dependent on inactivation of FOXO1 (PMID:16670089)
• versatile nature of FOXO1A in the regulation of a number of decidualization-specific genes (PMID:16690806)
• Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. (PMID:16709600)
• Expression of FOXO1A inhibited, and its knockdown promoted, cell proliferation or survival in prostate cancer. FOXO1A inhibited androgen- and androgen receptor-mediated gene regulation and cell proliferation. (PMID:16849544)
• FOXO1 and SREBP-1c have roles in insulin regulation of cholesterol 7alpha-hydroxylase expression (PMID:16885156)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxo1b	ENSDARG00000061549
danio_rerio	foxo1a	ENSDARG00000099555
mus_musculus	Foxo1	ENSMUSG00000044167
rattus_norvegicus	Foxo1	ENSRNOG00000013397

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), 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 O1 — Q12778 (reviewed: Q12778)

Alternative names: Forkhead box protein O1A, Forkhead in rhabdomyosarcoma

All UniProt accessions (1): Q12778

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. Binds to the insulin response element (IRE) with consensus sequence 5’-TT[G/A]TTTTG-3’ and the related Daf-16 family binding element (DBE) with consensus sequence 5’-TT[G/A]TTTAC-3’. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. 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. Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. Acts as an inhibitor of glucose sensing in pancreatic beta cells by acting as a transcription repressor and suppressing expression of PDX1. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1. Also promotes gluconeogenesis by directly promoting expression of PPARGC1A and G6PC1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1. Promotes neural cell death. Mediates insulin action on adipose tissue. Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells. Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner. Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling. Positive regulator of apoptosis in cardiac smooth muscle cells as a result of its transcriptional activation of pro-apoptotic genes. Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis.

Subunit / interactions. Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import. Interacts (acetylated form) with PPARG. Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway. Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteasomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1. Interacts with CRY1. Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity. Interacts with TOX4; FOXO1 is required for full induction of TOX4-dependent activity and the interaction is inhibited by insulin. Interacts (when phosphorylated on Ser-256) with STUB1/CHIP. Interacts with CTDSPL2.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in umbilical endothelial cells (at protein level). Abundantly expressed in skeletal muscle and ovary, with lower expression in the heart, placenta, lung, liver, pancreas, spleen, testis and small intestine. Weakly expressed in the brain, thymus, prostate and mucosal lining of the colon.

Post-translational modifications. Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention. Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation on Ser-256. Dephosphorylated at Ser-256 by CTDSPL2. Ubiquitinated by SKP2. Ubiquitination leads to proteasomal degradation. Ubiquitinated by STUB1/CHIP; when Ser-256 is phosphorylated. Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress. Acetylated. Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death. Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation. Acetylated at Lys-423, promoting its localization to the nucleus and transcription factor activity. Deacetylation at Lys-423 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity. Deacetylation and subsequent inhibition by SIRT6 has different effects depending on cell types: it inhibits gluconeogenesis in hepatocytes, promotes glucose sensing in pancreatic beta-cells and regulates lipid catabolism in brown adipocytes.

Disease relevance. Rhabdomyosarcoma 2 (RMS2) [MIM:268220] A form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchymal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. The gene represented in this entry may be involved in disease pathogenesis. Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.

Induction. Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter.

RefSeq proteins (1): NP_002006* (*=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
IPR047408	FH_FOXO1	Domain

Pfam: PF00250, PF16675, PF16676

UniProt features (71 total): modified residue 22, mutagenesis site 18, region of interest 8, compositionally biased region 5, strand 4, helix 4, site 3, short sequence motif 2, sequence conflict 2, chain 1, DNA-binding region 1, turn 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8A62	X-RAY DIFFRACTION	1.6
8A65	X-RAY DIFFRACTION	1.6
6QZS	X-RAY DIFFRACTION	1.9
3CO6	X-RAY DIFFRACTION	2.1
4LG0	X-RAY DIFFRACTION	2.19
3COA	X-RAY DIFFRACTION	2.2
6QZR	X-RAY DIFFRACTION	2.3
5DUI	X-RAY DIFFRACTION	2.31
3CO7	X-RAY DIFFRACTION	2.91
6LBI	X-RAY DIFFRACTION	3.07
6QVW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12778-F1	51.76	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.

Catalytic / active sites (3): 158 (dna-binding); 165 (dna-binding); 225 (dna-binding)

Post-translational modifications (22): 24, 212, 218, 234, 235, 245, 248, 249, 251, 253, 256, 262, 265, 274, 287, 298, 319, 322, 325, 329 …

Mutagenesis-validated functional residues (18):

Position	Phenotype
24	abolishes pkb/akt1-mediated phosphorylation but does not prevent phosphorylation of ser-256 or ser-319. also inhibits bi
212	abolishes stk4/mst1-mediated phosphorylation.
245	disrupts dna-binding; when associated with a-248.
248	disrupts dna-binding; when associated with a-245.
249	impaired phosphorylation by cdk1.
249	no effect on dna-binding.
251–253	no targeting to the nucleus and disruption of dna-binding.
256	completely abolishes pkb/akt1-mediated phosphorylation at all three sites, and inhibits binding of 14-3-3 proteins. inhi
256	reduces dna binding, promotes nuclear exclusion and partially promotes t-24 and s-319 phosphorylation. reduces dna bindi
262	inhibits interaction with atg7 and foxo1-acetylation-induced autophagic cell death; when associated with r-265 and r-274
265	inhibits interaction with atg7 and foxo1-acetylation-induced autophagic cell death; when associated with r-262 and r-274
274	inhibits interaction with atg7 and foxo1-acetylation-induced autophagic cell death; when associated with r-262 and r-265
319	abolishes pkb/akt1-mediated phosphorylation but does not prevent phosphorylation of ser-24 or ser-256. inhibits the pkb/
329	targeted to the nucleus and enhances transactivation.
423	abolished deacetylation by sirt6.
446	does not affect deacetylation by sirt6.
463	does not affect deacetylation by sirt6.
515	does not affect deacetylation by sirt6.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-198693	AKT phosphorylates targets in the nucleus
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-211163	AKT-mediated inactivation of FOXO1A
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-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

MSigDB gene sets: 617 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GU_PDEF_TARGETS_DN, GOBP_RESPONSE_TO_COLD, GOBP_REGULATION_OF_STRESS_ACTIVATED_PROTEIN_KINASE_SIGNALING_CASCADE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_INSULIN_SECRETION, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (46): blood vessel development (GO:0001568), temperature homeostasis (GO:0001659), intracellular glucose homeostasis (GO:0001678), regulation of transcription by RNA polymerase II (GO:0006357), protein acetylation (GO:0006473), autophagy (GO:0006914), apoptotic process (GO:0006915), DNA damage response (GO:0006974), insulin receptor signaling pathway (GO:0008286), cellular response to starvation (GO:0009267), gene expression (GO:0010467), positive regulation of autophagy (GO:0010508), cellular response to insulin stimulus (GO:0032869), negative regulation of stress-activated MAPK cascade (GO:0032873), positive regulation of smooth muscle cell apoptotic process (GO:0034393), cellular response to oxidative stress (GO:0034599), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), fat cell differentiation (GO:0045444), negative regulation of fat cell differentiation (GO:0045599), positive regulation of gluconeogenesis (GO:0045722), positive regulation of protein catabolic process (GO:0045732), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of insulin secretion (GO:0046676), canonical Wnt signaling pathway (GO:0060070), regulation of transcription initiation by RNA polymerase II (GO:0060260), cellular response to cold (GO:0070417), response to fatty acid (GO:0070542), cellular response to hyperoxia (GO:0071455), cellular response to nitric oxide (GO:0071732), negative regulation of canonical Wnt signaling pathway (GO:0090090), energy homeostasis (GO:0097009), neuronal stem cell population maintenance (GO:0097150), negative regulation of cardiac muscle hypertrophy in response to stress (GO:1903243), regulation of neural precursor cell proliferation (GO:2000177), regulation of reactive oxygen species metabolic process (GO:2000377), negative regulation of transcription by RNA polymerase II (GO:0000122), gluconeogenesis (GO:0006094)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nucleic acid binding (GO:0003676), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), sequence-specific DNA binding (GO:0043565), protein phosphatase 2A binding (GO:0051721), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
FOXO-mediated transcription	5
PIP3 activates AKT signaling	1
Regulation of beta-cell development	1
Regulation of gene expression in beta cells	1
PI3K/AKT Signaling in Cancer	1
MAPK family signaling cascades	1
Signaling by Interleukins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	4
binding	3
regulation of DNA-templated transcription	2
cellular response to stress	2
apoptotic process	2
regulation of apoptotic process	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
DNA binding	2
chromatin binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
vasculature development	1
anatomical structure development	1
multicellular organismal-level homeostasis	1
glucose homeostasis	1
intracellular chemical homeostasis	1
transcription by RNA polymerase II	1
protein acylation	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
cellular response to nutrient levels	1
response to starvation	1
macromolecule biosynthetic process	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
response to insulin	1
cellular response to peptide hormone stimulus	1
regulation of stress-activated MAPK cascade	1
negative regulation of MAPK cascade	1
stress-activated MAPK cascade	1
negative regulation of stress-activated protein kinase signaling cascade	1
positive regulation of muscle cell apoptotic process	1

Protein interactions and networks

STRING

5170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXO1	PPARGC1A	Q9UBK2	997
FOXO1	ATG7	O95352	993
FOXO1	SIRT1	Q96EB6	984
FOXO1	CTNNB1	P35222	984
FOXO1	CEBPA	P49715	974
FOXO1	HNF4A	P41235	947
FOXO1	AKT1	P31749	941
FOXO1	PAX7	P23759	923
FOXO1	CEBPB	P17676	922
FOXO1	PAX3	P23760	921
FOXO1	CREB1	P16220	912
FOXO1	INS	P01308	910
FOXO1	IGF1	P01343	908
FOXO1	SIRT2	Q8IXJ6	896
FOXO1	PTEN	P60484	895

IntAct

102 interactions, top by confidence:

A	B	Type	Score
CCNB1	CDK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
FOXO1	YWHAZ	psi-mi:“MI:0914”(association)	0.790
SIRT1	FOXO1	psi-mi:“MI:0915”(physical association)	0.700
FOXO1	SIRT1	psi-mi:“MI:0915”(physical association)	0.700
CDK1	FOXO1	psi-mi:“MI:0217”(phosphorylation reaction)	0.650
FOXO1	CDK1	psi-mi:“MI:0915”(physical association)	0.650
CDK1	FOXO1	psi-mi:“MI:0915”(physical association)	0.650
FOXO1	CDK1	psi-mi:“MI:0407”(direct interaction)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
FOXO1	FHL2	psi-mi:“MI:0915”(physical association)	0.640
FHL2	FOXO1	psi-mi:“MI:0915”(physical association)	0.640
FHL2	FOXO1	psi-mi:“MI:0403”(colocalization)	0.640
FOXO1	YWHAE	psi-mi:“MI:0915”(physical association)	0.620
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
SET	FOXO1	psi-mi:“MI:0915”(physical association)	0.590
FOXO1	SET	psi-mi:“MI:0915”(physical association)	0.590
FOXO1	AKT1	psi-mi:“MI:0407”(direct interaction)	0.570

BioGRID (442): FHL2 (Affinity Capture-Western), FOXO1 (Affinity Capture-Western), FOXO1 (Reconstituted Complex), FOXO1 (Affinity Capture-Western), SIRT1 (Affinity Capture-Western), FOXO1 (Biochemical Activity), FOXO1 (Biochemical Activity), FOXO1 (Biochemical Activity), FOXO1 (Biochemical Activity), FOXO1 (Biochemical Activity), EP300 (Reconstituted Complex), FOXO1 (Affinity Capture-Western), EP300 (Affinity Capture-Western), FOXO1 (Biochemical Activity), YWHAQ (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

83 interactions.

A	Effect	B	Mechanism
AKT1	down-regulates	FOXO1	phosphorylation
DYRK1A	“down-regulates activity”	FOXO1	phosphorylation
FOXO1	“up-regulates quantity by expression”	G6PC1	“transcriptional regulation”
FOXO1	down-regulates	PPARGC1A
CDK2	down-regulates	FOXO1	phosphorylation
FOXO1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
FOXO1	“up-regulates quantity by expression”	CDKN2D	“transcriptional regulation”
PRKAA1	up-regulates	FOXO1	phosphorylation
STK4	up-regulates	FOXO1	phosphorylation
CDK1	down-regulates	FOXO1	phosphorylation
FOXO1	“down-regulates quantity by repression”	GK	“transcriptional regulation”
CSNK1A1	down-regulates	FOXO1	phosphorylation
DYRK1A	down-regulates	FOXO1	phosphorylation
DUSP6	up-regulates	FOXO1	dephosphorylation
FOXO1	“up-regulates quantity by expression”	PCK1	“transcriptional regulation”
AKT1	“down-regulates quantity by destabilization”	FOXO1	phosphorylation
FOXO1	“up-regulates quantity by expression”	BCL2L11	“transcriptional regulation”
AMPK	up-regulates	FOXO1	phosphorylation
FOXO1	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
FOXO1	“up-regulates quantity by expression”	FBXO32	“transcriptional regulation”
AKT	“down-regulates activity”	FOXO1	phosphorylation
SIRT1	“up-regulates activity”	FOXO1	deacetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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	152.3×	1e-14
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	151.2×	4e-16
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	134.3×	3e-14
Activation of BH3-only proteins	8	99.3×	4e-13
FOXO-mediated transcription	10	84.0×	3e-15
RHO GTPases activate PKNs	8	63.4×	2e-11
Intrinsic Pathway for Apoptosis	8	58.6×	4e-11
Transcriptional and post-translational regulation of MITF-M expression and activity	9	40.1×	4e-11

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	41.6×	5e-05
epidermal growth factor receptor signaling pathway	5	28.2×	2e-04
intracellular protein localization	7	16.6×	5e-05
negative regulation of gene expression	7	11.0×	4e-04
in utero embryonic development	5	8.2×	8e-03
protein phosphorylation	5	7.7×	8e-03
negative regulation of apoptotic process	8	6.3×	1e-03
positive regulation of gene expression	7	6.2×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — BL, LUSC, MLYM, NHL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	71
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2574035	NM_002015.4(FOXO1):c.482G>A (p.Gly161Asp)	Pathogenic

SpliceAI

1922 predictions. Top by Δscore:

Variant	Effect	Δscore
13:40569520:T:C	donor_gain	1.0000
13:40569529:T:TA	donor_gain	1.0000
13:40645379:T:TA	donor_gain	1.0000
13:40645395:C:A	donor_gain	1.0000
13:40560856:GAATT:G	acceptor_gain	0.9900
13:40560859:TT:T	acceptor_gain	0.9900
13:40560861:C:CA	acceptor_loss	0.9900
13:40560861:C:CC	acceptor_gain	0.9900
13:40569526:ACTT:A	donor_gain	0.9900
13:40569527:CTTC:C	donor_gain	0.9900
13:40569530:C:A	donor_gain	0.9900
13:40633262:C:T	acceptor_gain	0.9900
13:40633267:C:CT	acceptor_gain	0.9900
13:40633268:A:T	acceptor_gain	0.9900
13:40645394:C:CA	donor_gain	0.9900
13:40649909:A:AC	donor_gain	0.9900
13:40665579:TCAC:T	donor_loss	0.9900
13:40665580:CACCT:C	donor_loss	0.9900
13:40665581:ACCTT:A	donor_gain	0.9900
13:40665582:C:A	donor_loss	0.9900
13:40665582:CCTT:C	donor_gain	0.9900
13:40665582:CCTTC:C	donor_gain	0.9900
13:40560858:ATT:A	acceptor_gain	0.9800
13:40645391:ACTCC:A	donor_gain	0.9800
13:40645392:CTCCC:C	donor_gain	0.9800
13:40665581:A:AC	donor_gain	0.9800
13:40665582:C:CC	donor_gain	0.9800
13:40665616:AT:A	donor_gain	0.9800
13:40558563:C:CT	acceptor_gain	0.9700
13:40560857:AATT:A	acceptor_gain	0.9700

AlphaMissense

4334 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:40560735:T:A	R252S	1.000
13:40560735:T:G	R252S	1.000
13:40560738:C:A	R251S	1.000
13:40560738:C:G	R251S	1.000
13:40560739:C:A	R251M	1.000
13:40560739:C:G	R251T	1.000
13:40560780:C:A	W237C	1.000
13:40560780:C:G	W237C	1.000
13:40560781:C:G	W237S	1.000
13:40560782:A:G	W237R	1.000
13:40560782:A:T	W237R	1.000
13:40560783:C:A	W236C	1.000
13:40560783:C:G	W236C	1.000
13:40560785:A:G	W236R	1.000
13:40560785:A:T	W236R	1.000
13:40560787:G:A	S235F	1.000
13:40560789:A:C	S234R	1.000
13:40560789:A:T	S234R	1.000
13:40560790:C:A	S234I	1.000
13:40560791:T:G	S234R	1.000
13:40560792:T:A	K233N	1.000
13:40560792:T:G	K233N	1.000
13:40560793:T:A	K233I	1.000
13:40560794:T:C	K233E	1.000
13:40560794:T:G	K233Q	1.000
13:40560796:C:T	G232E	1.000
13:40560797:C:G	G232R	1.000
13:40560797:C:T	G232R	1.000
13:40560818:G:T	R225S	1.000
13:40560822:G:C	F223L	1.000

dbSNP variants (sampled 300 via entrez): RS1000006865 (13:40624542 G>A), RS1000053287 (13:40664506 CCTT>C), RS1000075219 (13:40628596 C>T), RS1000110174 (13:40618130 G>A), RS1000150540 (13:40633847 G>A), RS1000169450 (13:40659004 TC>T), RS1000182187 (13:40634209 A>G), RS1000212105 (13:40589793 A>C), RS1000224696 (13:40652862 T>A), RS1000262095 (13:40615563 ACATACATACATACAG>A), RS1000280523 (13:40612087 CAAATAA>C,CAAATAAAAATAA), RS1000347746 (13:40564090 G>T), RS1000364947 (13:40606206 C>T), RS1000403904 (13:40628356 T>C), RS1000443153 (13:40624254 A>C)

Disease associations

OMIM: gene MIM:136533 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): diffuse large B-cell lymphoma (MONDO:0018905)

Orphanet (1): Diffuse large B-cell lymphoma (Orphanet:544)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001442	Typified by somatic mosaicism
HP:0006779	Alveolar rhabdomyosarcoma

GWAS associations

46 associations (top):

Study	Trait	p-value
GCST000683_2	Central corneal thickness	5.000000e-10
GCST000775_2	Central corneal thickness	1.000000e-08
GCST001806_19	Corneal structure	4.000000e-14
GCST004600_11	Eosinophil percentage of white cells	2.000000e-15
GCST004602_168	Mean corpuscular volume	7.000000e-12
GCST004606_75	Eosinophil count	1.000000e-13
GCST004608_188	Granulocyte percentage of myeloid white cells	3.000000e-20
GCST004609_204	Monocyte percentage of white cells	1.000000e-16
GCST004617_148	Eosinophil percentage of granulocytes	2.000000e-10
GCST004624_150	Sum eosinophil basophil counts	3.000000e-13
GCST004625_136	Monocyte count	4.000000e-15
GCST004630_191	Mean corpuscular hemoglobin	7.000000e-09
GCST005038_82	Allergic disease (asthma, hay fever or eczema)	7.000000e-12
GCST005170_9	Intraocular pressure	8.000000e-18
GCST005580_235	Intraocular pressure	5.000000e-17
GCST005580_243	Intraocular pressure	2.000000e-16
GCST005667_6	Central corneal thickness	3.000000e-16
GCST005993_8	Mean corpuscular hemoglobin	7.000000e-23
GCST005996_39	Red blood cell count	1.000000e-14
GCST006011_39	Mean corpuscular volume	2.000000e-25
GCST006462_53	Uterine fibroids	7.000000e-08
GCST006979_1096	Heel bone mineral density	2.000000e-19
GCST007846_2	Arterial stiffness	9.000000e-09
GCST008152_137	Weight	6.000000e-06
GCST008276_4	Corneal resistance factor	5.000000e-11
GCST008277_3	Corneal hysteresis	5.000000e-11
GCST008315_4	Corneal hysteresis	7.000000e-07
GCST008318_6	Corneal resistance factor	1.000000e-09
GCST008403_20	Arterial stiffness index	2.000000e-11
GCST009158_3	Uterine fibroids	6.000000e-14

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0004345	corneal topography
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0004305	erythrocyte count
EFO:0009270	heel bone mineral density
EFO:0004517	arterial stiffness measurement
EFO:0004338	body weight
EFO:0010067	corneal resistance factor
EFO:0010066	corneal hysteresis
EFO:0010379	phosphatidylcholine 36:1 measurement
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5169275 (CHIMERIC PROTEIN), CHEMBL5294 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,666 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL483254	PANOBINOSTAT	4	11,666

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs144991623	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

ChEMBL bioactivities

26 potent at pChembl≥5 of 33 total, top 26 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.48	IC50	33	nM	CHEMBL5192734
6.38	EC50	420	nM	PANOBINOSTAT
6.00	IC50	1000	nM	CHEMBL5410786
6.00	IC50	1000	nM	CHEMBL5427016
6.00	IC50	1000	nM	CHEMBL5430492
6.00	IC50	1000	nM	CHEMBL5438402
6.00	IC50	1000	nM	CHEMBL5422565
6.00	IC50	1000	nM	CHEMBL5401913
6.00	IC50	1000	nM	CHEMBL5416762
6.00	IC50	1000	nM	CHEMBL5432660
6.00	IC50	1000	nM	CHEMBL5440152
6.00	IC50	1000	nM	CHEMBL5435132
6.00	IC50	1000	nM	CHEMBL5435547
6.00	IC50	1000	nM	CHEMBL5433566
6.00	IC50	1000	nM	CHEMBL5424486
6.00	IC50	1000	nM	CHEMBL5423837
6.00	IC50	1000	nM	CHEMBL5410704
6.00	IC50	1000	nM	CHEMBL5405275
6.00	IC50	1000	nM	CHEMBL5440878
6.00	IC50	1000	nM	CHEMBL5413713
5.30	IC50	5000	nM	PSAMMAPLYSENE A
5.27	IC50	5400	nM	CHEMBL5411675
5.24	IC50	5700	nM	CHEMBL5399207
5.19	IC50	6400	nM	CHEMBL5423897
5.03	IC50	9400	nM	CHEMBL5411675
5.01	IC50	9800	nM	CHEMBL5399207

PubChem BioAssay actives

8 with measured affinity, of 41 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid	1892082: Inhibition of FOXO-1 in human HepG2 cells incubated for 20 hrs by Renilla luciferase reporter gene assay	ic50	0.0330	uM
Panobinostat	2138368: Activation of FoxO1(unknown origin)	ec50	0.4200	uM
(E)-N-[3-[2,6-dibromo-4-[2-(dimethylamino)ethyl]phenoxy]propyl]-3-[3,5-dibromo-4-[3-(dimethylamino)propoxy]phenyl]prop-2-enamide	377823: Inhibition of FOXO1a nuclear export in PTEN-deficient cells	ic50	5.0000	uM
(8-hydroxy-7-methoxy-2,6-dimethylisoquinolin-2-ium-5-yl) 2-[(7-methoxy-2,6-dimethyl-3,5,8-trioxoisoquinolin-4-yl)amino]ethanesulfonate	2006657: Inhibition of PAX3-FOXO1 (unknown origin) fusion protein expressed human Rh4 cells cotransfected with ALK-Luc incubated for 24 hrs by Steady-Glo luciferase assay	ic50	5.4000	uM
8-hydroxy-7-methoxy-5-[2-[(7-methoxy-2,6-dimethyl-3,5,8-trioxoisoquinolin-4-yl)amino]ethylsulfonyloxy]-2,6-dimethylisoquinolin-2-ium-3-carboxylic acid	2006657: Inhibition of PAX3-FOXO1 (unknown origin) fusion protein expressed human Rh4 cells cotransfected with ALK-Luc incubated for 24 hrs by Steady-Glo luciferase assay	ic50	5.7000	uM
methyl 8-hydroxy-7-methoxy-5-[2-[(7-methoxy-2,6-dimethyl-3,5,8-trioxoisoquinolin-4-yl)amino]ethylsulfonyloxy]-2,6-dimethylisoquinolin-2-ium-3-carboxylate	2006657: Inhibition of PAX3-FOXO1 (unknown origin) fusion protein expressed human Rh4 cells cotransfected with ALK-Luc incubated for 24 hrs by Steady-Glo luciferase assay	ic50	6.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases expression, decreases response to substance, decreases phosphorylation, decreases ubiquitination, affects localization (+8 more)	6
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	6
Dexamethasone	affects cotreatment, affects phosphorylation, affects reaction, decreases phosphorylation, decreases reaction (+1 more)	5
Hydrogen Peroxide	affects cotreatment, increases expression, affects localization, decreases reaction, decreases phosphorylation	5
Medroxyprogesterone Acetate	increases localization, increases reaction, decreases reaction, increases secretion, affects cotreatment (+3 more)	5
Cadmium Chloride	decreases reaction, increases abundance, increases localization, increases phosphorylation, decreases expression (+2 more)	5
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, increases expression, decreases phosphorylation, decreases reaction, decreases localization (+1 more)	4
Wortmannin	decreases reaction, increases phosphorylation, affects localization, increases expression	4
Arsenic Trioxide	increases expression, affects cotreatment, decreases phosphorylation	4
Estradiol	affects expression, affects cotreatment, increases expression, affects binding, decreases reaction (+1 more)	4
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	affects localization, decreases expression, increases expression	3
pyrazolanthrone	increases localization, increases phosphorylation, decreases reaction, increases abundance	3
dorsomorphin	affects cotreatment, increases expression, decreases expression, decreases reaction, affects localization (+2 more)	3
Cadmium	increases reaction, decreases reaction, increases abundance, increases localization, increases phosphorylation (+2 more)	3
afuresertib	decreases phosphorylation, affects cotreatment, affects phosphorylation, affects reaction	2
caryophyllene	affects cotreatment, increases expression, affects localization, decreases reaction	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases phosphorylation, increases response to substance	2
5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid	decreases reaction, increases expression, increases phosphorylation	2
Panobinostat	affects cotreatment, increases expression	2
Cyclic AMP	decreases reaction, increases expression, affects cotreatment	2
Benzo(a)pyrene	affects activity, decreases methylation	2
Calcitriol	increases expression, decreases expression	2
Cisplatin	affects cotreatment, decreases phosphorylation, decreases expression	2
Copper	affects binding, increases expression, affects localization, increases phosphorylation, decreases reaction	2
Bucladesine	affects cotreatment, increases expression, increases localization, increases reaction	2
Progesterone	increases expression, affects binding, affects cotreatment, decreases reaction, increases reaction	2
Tamoxifen	affects reaction, increases expression, affects expression, affects cotreatment, decreases expression	2

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5128651	Binding	Inhibition of PAX3-FOXO1 driven transcriptional activity in human Rh4 cells transfected with ALK-Luc construct incubated for 24 hrs by luciferase assay	Dentithecamides A-H, Diacylated Zoanthoxanthin Derivatives with PAX3-FOXO1 Inhibitory Activity from the Hydroid Dentitheca habereri. — J Nat Prod

Cellosaurus cell lines

32 cell lines: 30 cancer cell line, 2 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0041	Rh30	Cancer cell line	Male
CVCL_1659	Rh18	Cancer cell line	Female
CVCL_2176	Rh41	Cancer cell line	Female
CVCL_4871	NRS-1	Cancer cell line	Female
CVCL_5916	Rh4	Cancer cell line	Female
CVCL_5917	Rh5	Cancer cell line	Sex unspecified
CVCL_7952	CW12	Cancer cell line	Sex unspecified
CVCL_8670	Rh41-807R	Cancer cell line	Female
CVCL_8751	Rh41-MAB391R	Cancer cell line	Female
CVCL_8752	Rh28	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00466258	PHASE4	COMPLETED	LINFOTARGAM: Treatment With Chemotherapy Plus Rituximab and Highly Active Antiretroviral Therapy in Patients With Diffuse Large B Cell Lymphoma and Infection With the Human Immunodeficiency Virus (HIV)
NCT01949818	PHASE4	UNKNOWN	Treatment of Diffuse Large B Cell Lymphoma
NCT02752815	PHASE4	UNKNOWN	Reduced Chemotherapy in Low Risk DLBCL
NCT03376958	PHASE4	COMPLETED	Apatinib for Relapsed and Refractory Diffuse Large B Cell Lymphoma
NCT03513601	PHASE4	UNKNOWN	Treatment of Elderly Patients With Diffuse Large B-cell Lymphoma
NCT03579082	PHASE4	UNKNOWN	A Clinical Trial of Decitabine in Relapse and Refractory Diffuse Large B Cell Lymphoma
NCT05108805	PHASE4	COMPLETED	Chimeric Antigen Receptor (CAR) T Cell Therapy With YESCARTA in the Outpatient Setting
NCT05518383	PHASE4	RECRUITING	B-cell Mature Non-Hodgkin’s Lymphoma Treatment Protocol in Children and Adolescents 2021
NCT00075478	PHASE3	COMPLETED	Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
NCT00355199	PHASE3	COMPLETED	Comparison of HD Chemotherapy Followed by Auto-transplant and R-CHOP in High Risk Patients With DLBCL.
NCT00400478	PHASE3	COMPLETED	A Multicentre, Randomized Phase III Study of Rituximab as Maintenance Treatment Versus Observation in Patients With Aggressive B-cell Lymphoma: NHL-13
NCT00499018	PHASE3	UNKNOWN	Dose Dense Chemotherapy + Rituximab +/-Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cell in Diffuse Large B-Cell Lymphoma
NCT00790036	PHASE3	COMPLETED	Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-chemotherapy
NCT00846157	PHASE3	UNKNOWN	Biocell Natural Killer Mixture in Diffuse Large B Cell Lymphoma (DLBCL) Patients
NCT01122472	PHASE3	COMPLETED	Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP
NCT01148446	PHASE3	COMPLETED	R-CHOP Versus R-mini-CEOP in Elderly Patients(>65)With DLBCL
NCT01231412	PHASE3	COMPLETED	Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant
NCT01285765	PHASE3	COMPLETED	Evaluate a Treatment Adapted to the PET Response Compared to a Standard Treatment, for Low Risk DLBCL CD 20+ Patients
NCT01287741	PHASE3	TERMINATED	A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA)
NCT01321541	PHASE3	COMPLETED	Comparison of Pixantrone + Rituximab With Gemcitabine + Rituximab in Patients With Aggressive B-cell Non-Hodgkin Lymphoma or Follicular Grade 3 Lymphoma Who Have Relapsed After Therapy and Are Not Eligible for Stem Cell Transplant
NCT01459887	PHASE3	COMPLETED	Study of Recombinant Human-Mouse Chimeric Anti-CD20 Monoclonal Antibody to Treat Non-hodgkin’s Lymphoma
NCT01510184	PHASE3	TERMINATED	Study of Zevalin Versus Observation in Participants at Least 60 Years Old With Newly Diagnosed Diffuse Large B-cell Lymphoma in Positron Emission Tomography (PET)-Negative Complete Remission After Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) or R-CHOP-like Therapy
NCT01804686	PHASE3	RECRUITING	A Long-term Extension Study of PCI-32765 (Ibrutinib)
NCT01852435	PHASE3	UNKNOWN	R-CEOP-90/R-CEOP-70 Versus R-CHOP-50 in the Treatment of Diffuse Large B-cell Lymphoma and Follicular Lymphoma Grade 3B
NCT02054559	PHASE3	WITHDRAWN	R-CHOP Alone vs. R-CHOP Plus Radiotherapy for Localized CD20+ DLBCL
NCT02128061	PHASE3	COMPLETED	Efficacy of Lenalidomide in Combination With Subcutaneous Rituximab + miniCHOP in DLBCL Patients of 80 y/o or+
NCT02268045	PHASE3	COMPLETED	Study of RTXM83 Plus CHOP Chemotherapy Versus a Rituximab Plus CHOP Therapy in Patients With Non Hodgkin’s Lymphoma
NCT02366663	PHASE3	TERMINATED	BEAM vs. 90-Yttrium Ibritumomab Tiuxetan (Zevalin®)/BEAM With ASCT for Relapsed DLBCL
NCT02449265	PHASE3	UNKNOWN	Efficacy of Consolidative Involved-site Radiotherapy for Patients With Limited-stage Diffuse Large B-cell Lymphoma
NCT02449278	PHASE3	UNKNOWN	The Palliative Benefit of Involved-site Radiotherapy for Patients With Advanced-stage Diffuse Large B-cell Lymphoma
NCT02531841	PHASE3	UNKNOWN	High-dose Chemotherapy and ASCT or Consolidating Conventional Chemotherapy in Primary CNS Lymphoma
NCT02617485	PHASE3	COMPLETED	MabionCD20 Compared to MabThera in Lymphoma Patients
NCT02767674	PHASE3	UNKNOWN	Trial of R-GemOx Versus R-miniCHOP Regimen in First-line Treatment of Elderly Diffuse Large B Cell Lymphoma
NCT02772822	PHASE3	UNKNOWN	A Study Comparing the Efficiency and Safety of S-CHOP(Cyclophosphamide, Hydroxydaunomycin, Oncovin, and Prednisone) Versus R-CHOP in Untreated CD20(Cluster of Differentiation Antigen 20)-Positive DLBCL Patients
NCT02777736	PHASE3	UNKNOWN	CNS Prophylaxis in Diffuse Large B-cell Lymphoma
NCT02842931	PHASE3	UNKNOWN	R-Dose-adjusted (DA) - EPOCH-21 Versus R-modified Non-Hodgkin Lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM)-90 Program (mNHL-BFM-90) and Autologous Stem Cells Transplantation (Auto-SCT) in DLBCL With Poor Prognosis
NCT02951156	PHASE3	TERMINATED	Avelumab In Combination Regimens That Include An Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL)
NCT03123718	PHASE3	UNKNOWN	High-dose Intravenous Methotrexate Versus Intrathecal Methotrexate for Central Nervous System Prophylaxis in DLBCL
NCT03151044	PHASE3	UNKNOWN	R±CEOP90 Versus R±CEOP75 in Newly Diagnosed Young Patients With Medium/High-risk DLBCL
NCT03213977	PHASE3	UNKNOWN	R-DA-EDOCH Versus R-CEOP90, With/Without Upfront Auto-HSCT in Young Patients With High-risk DLBCL