FOXO4 (forkhead box O4)

Gene

• Entrez ID: 4303
• Gene name: Forkhead box O4
• Gene symbol: FOXO4
• Synonyms (NCBI Gene): AFX, AFX1, MLLT7
• Chromosome: X
• Chromosome location: Xq13.1
• Summary: This gene encodes a member of the O class of winged helix/forkhead transcription factor family. Proteins encoded by this class are regulated by factors involved in growth and differentiation indicating they play a role in these processes. A translocation

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT006698	hsa-miR-499a-5p	Luciferase reporter assay, qRT-PCR, Western blot	21934092
MIRT018590	hsa-miR-335-5p	Microarray	18185580
MIRT039705	hsa-miR-615-3p	CLASH	23622248
MIRT437900	hsa-miR-421	Luciferase reporter assay, Western blot	23707940
MIRT437900	hsa-miR-421	Luciferase reporter assay, Western blot	23707940
MIRT1003121	hsa-miR-3163	CLIP-seq
MIRT1003122	hsa-miR-340	CLIP-seq
MIRT1003123	hsa-miR-4452	CLIP-seq
MIRT1003124	hsa-miR-4729	CLIP-seq
MIRT1003125	hsa-miR-514	CLIP-seq
MIRT1003126	hsa-miR-514b-3p	CLIP-seq
MIRT1003127	hsa-miR-548n	CLIP-seq
MIRT1003128	hsa-miR-548t	CLIP-seq
MIRT1003129	hsa-miR-561	CLIP-seq
MIRT1003130	hsa-miR-579	CLIP-seq
MIRT1003131	hsa-miR-664	CLIP-seq
MIRT1003132	hsa-miR-1184	CLIP-seq
MIRT1003133	hsa-miR-1205	CLIP-seq
MIRT1003134	hsa-miR-23a	CLIP-seq
MIRT1003135	hsa-miR-23b	CLIP-seq
MIRT1003136	hsa-miR-23c	CLIP-seq
MIRT1003137	hsa-miR-3158-5p	CLIP-seq
MIRT1003138	hsa-miR-3164	CLIP-seq
MIRT1003139	hsa-miR-3614-3p	CLIP-seq
MIRT1003140	hsa-miR-4263	CLIP-seq
MIRT1003141	hsa-miR-4299	CLIP-seq
MIRT1003142	hsa-miR-4521	CLIP-seq
MIRT1003143	hsa-miR-4652-3p	CLIP-seq
MIRT1003144	hsa-miR-4686	CLIP-seq
MIRT1003145	hsa-miR-617	CLIP-seq
MIRT1997423	hsa-miR-1275	CLIP-seq
MIRT1997424	hsa-miR-1292	CLIP-seq
MIRT1997425	hsa-miR-149	CLIP-seq
MIRT1997426	hsa-miR-1909	CLIP-seq
MIRT1997427	hsa-miR-214	CLIP-seq
MIRT1997428	hsa-miR-3619-5p	CLIP-seq
MIRT1997429	hsa-miR-4471	CLIP-seq
MIRT1997430	hsa-miR-4651	CLIP-seq
MIRT1997431	hsa-miR-4665-5p	CLIP-seq
MIRT1997432	hsa-miR-608	CLIP-seq
MIRT1997433	hsa-miR-642b	CLIP-seq
MIRT1997434	hsa-miR-761	CLIP-seq
MIRT1997423	hsa-miR-1275	CLIP-seq
MIRT1997426	hsa-miR-1909	CLIP-seq
MIRT1997427	hsa-miR-214	CLIP-seq
MIRT2231091	hsa-miR-2355-5p	CLIP-seq
MIRT2231092	hsa-miR-3157-5p	CLIP-seq
MIRT2231093	hsa-miR-3191	CLIP-seq
MIRT1997428	hsa-miR-3619-5p	CLIP-seq
MIRT2231094	hsa-miR-4267	CLIP-seq
MIRT2231095	hsa-miR-4447	CLIP-seq
MIRT2231096	hsa-miR-4472	CLIP-seq
MIRT2231097	hsa-miR-4525	CLIP-seq
MIRT1997430	hsa-miR-4651	CLIP-seq
MIRT1997431	hsa-miR-4665-5p	CLIP-seq
MIRT2231098	hsa-miR-4691-3p	CLIP-seq
MIRT2231099	hsa-miR-4723-5p	CLIP-seq
MIRT2231100	hsa-miR-4728-5p	CLIP-seq
MIRT1997432	hsa-miR-608	CLIP-seq
MIRT2231101	hsa-miR-625	CLIP-seq
MIRT1997434	hsa-miR-761	CLIP-seq
MIRT2429019	hsa-miR-1284	CLIP-seq
MIRT2429020	hsa-miR-153	CLIP-seq
MIRT2429021	hsa-miR-3144-3p	CLIP-seq
MIRT2429022	hsa-miR-3684	CLIP-seq
MIRT2429023	hsa-miR-4684-5p	CLIP-seq
MIRT2429024	hsa-miR-4768-5p	CLIP-seq
MIRT2429025	hsa-miR-544	CLIP-seq
MIRT2429026	hsa-miR-875-5p	CLIP-seq
MIRT2429019	hsa-miR-1284	CLIP-seq
MIRT2429020	hsa-miR-153	CLIP-seq
MIRT2429021	hsa-miR-3144-3p	CLIP-seq
MIRT2429022	hsa-miR-3684	CLIP-seq
MIRT2429023	hsa-miR-4684-5p	CLIP-seq
MIRT2429024	hsa-miR-4768-5p	CLIP-seq
MIRT2429025	hsa-miR-544	CLIP-seq
MIRT2429026	hsa-miR-875-5p	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
TSC22D3	Repression	20018851

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000785	Component	Chromatin	ISA
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IBA
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISA
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	IDA	11689711
GO:0003676	Function	Nucleic acid binding	EXP	11352721
GO:0003677	Function	DNA binding	IDA	10783894
GO:0003677	Function	DNA binding	IEA
GO:0003700	Function	DNA-binding transcription factor activity	IDA	10783894
GO:0003700	Function	DNA-binding transcription factor activity	IEA
GO:0005515	Function	Protein binding	IPI	15084259, 15126506, 16114898, 25416956, 36931259
GO:0005634	Component	Nucleus	IBA
GO:0005634	Component	Nucleus	IDA	16272144, 16964248
GO:0005634	Component	Nucleus	IEA
GO:0005634	Component	Nucleus	TAS	22972301
GO:0005654	Component	Nucleoplasm	IEA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IDA	16964248
GO:0005737	Component	Cytoplasm	IEA
GO:0005829	Component	Cytosol	IDA	16272144
GO:0005829	Component	Cytosol	TAS	22972301
GO:0006355	Process	Regulation of DNA-templated transcription	IDA	15126506
GO:0006355	Process	Regulation of DNA-templated transcription	IEA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA
GO:0006979	Process	Response to oxidative stress	IDA	36075446
GO:0006979	Process	Response to oxidative stress	IDA	36075446
GO:0007095	Process	Mitotic G2 DNA damage checkpoint signaling	IEA
GO:0007517	Process	Muscle organ development	IEA
GO:0008013	Function	Beta-catenin binding	IDA	15905404
GO:0008013	Function	Beta-catenin binding	IEA
GO:0008285	Process	Negative regulation of cell population proliferation	IDA	10783894
GO:0008285	Process	Negative regulation of cell population proliferation	IEA
GO:0008286	Process	Insulin receptor signaling pathway	IDA	10217147
GO:0014911	Process	Positive regulation of smooth muscle cell migration	IEA
GO:0016525	Process	Negative regulation of angiogenesis	IDA	12761217
GO:0016607	Component	Nuclear speck	IDA
GO:0019899	Function	Enzyme binding	IPI	15126506, 16964248
GO:0030154	Process	Cell differentiation	IEA
GO:0031667	Process	Response to nutrient levels	IEA
GO:0034599	Process	Cellular response to oxidative stress	IDA	15601839, 36075446
GO:0042802	Function	Identical protein binding	IPI	25609649
GO:0043161	Process	Proteasome-mediated ubiquitin-dependent protein catabolic process	IDA	15601839
GO:0043565	Function	Sequence-specific DNA binding	IDA	23332764
GO:0043565	Function	Sequence-specific DNA binding	IEA
GO:0043565	Function	Sequence-specific DNA binding	IMP	22972301
GO:0045893	Process	Positive regulation of DNA-templated transcription	IEA
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	11689711, 15905404
GO:0048863	Process	Stem cell differentiation	IMP	22972301
GO:0051151	Process	Negative regulation of smooth muscle cell differentiation	IDA	16054032
GO:0070317	Process	Negative regulation of G0 to G1 transition	IDA	10783894
GO:0070936	Process	Protein K48-linked ubiquitination	IDA	36075446
GO:0140297	Function	DNA-binding transcription factor binding	IPI	16054032
GO:1990785	Process	Response to water-immersion restraint stress	IEA
GO:1990837	Function	Sequence-specific double-stranded DNA binding	IDA	28473536
GO:1990841	Function	Promoter-specific chromatin binding	IEA

Other IDs

• MIM: 300033
• HGNC: 7139
• e!Ensembl: ENSG00000184481

Protein

• UniProt ID: P98177
• Protein name: Forkhead box protein O4 (Fork head domain transcription factor AFX1)
• Protein function: Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcription
• PDB: 1E17, 3L2C
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00250	Forkhead	102 → 188	Forkhead domain	Domain
  PF16676	FOXO-TAD	463 → 504	Transactivation domain of FOXO protein family	Domain

• Tissue specificity: TISSUE SPECIFICITY: Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform zeta is most abundant in the liver, kidney, and pancreas.
• Sequence:

  MDPGNENSATEAAAIIDLDPDFEPQSRPRSCTWPLPRPEIANQPSEPPEVEPDLGEKVHT
  EGRSEPILLPSRLPEPAGGPQPGILGAVTGPRKGGSRRNAWGNQSYAELISQAIESAPEK
  RLTLAQIYEWMVRTVPYFKDKGDSNSSAGWKNSIRHNLSLHSKFIKVHNEATGKSSWWML
  NPEGGKSGKAPRRRAASMDSSSKLLRGRSKAPKKKPSVLPAPPEGATPTSPVGHFAKWSG
  SPCSRNREEADMWTTFRPRSSSNASSVSTRLSPLRPESEVLAEEIPASVSSYAGGVPPTL
  NEGLELLDGLNLTSSHSLLSRSGLSGFSLQHPGVTGPLHTYSSSLFSPAEGPLSAGEGCF
  SSSQALEALLTSDTPPPPADVLMTQVDPILSQAPTLLLLGGLPSSSKLATGVGLCPKPLE
  APGPSSLVPTLSMIAPPPVMASAPIPKALGTPVLTPPTEAASQDRMPQDLDLDMYMENLE
  CDMDNIISDLMDEGEGLDFNFEPDP

• Sequence length: 505

Pathways

KEGG:

Ras signaling pathway
FoxO signaling pathway
Shigellosis

Reactome:

AKT phosphorylates targets in the nucleus
Constitutive Signaling by AKT1 E17K in Cancer
Ub-specific processing proteases
Regulation of localization of FOXO transcription factors
FOXO-mediated transcription of cell death genes
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
FOXO-mediated transcription of cell cycle genes

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Abnormality of the face	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Clinodactyly	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Intellectual disability	Uncertain significance	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Macrocephaly	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Moderate intellectual disability	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Short 5th metacarpal	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
ABLEPHARON-MACROSTOMIA SYNDROME	Ablepharon macrostomia syndrome	BEFREE	30278484		★☆☆☆☆ Found in Text Mining only
Acute leukemia	Leukemia	BEFREE	9010221		★☆☆☆☆ Found in Text Mining only
Adult Diffuse Large B-Cell Lymphoma	B-cell Lymphoma	BEFREE	27911272		★☆☆☆☆ Found in Text Mining only
Angiofibroma	Angiofibroma	BEFREE	28274512		★☆☆☆☆ Found in Text Mining only
Aortic Aneurysm	Aortic Aneurysm	BEFREE	29089350		★☆☆☆☆ Found in Text Mining only
Aortic Aneurysm, Abdominal	Aortic Aneurysm	BEFREE	28431107, 29325136		★☆☆☆☆ Found in Text Mining only
Arteriosclerosis	Arteriosclerosis	BEFREE	31030940, 31255737		★☆☆☆☆ Found in Text Mining only
Arthritis	Arthritis	BEFREE	28011648		★☆☆☆☆ Found in Text Mining only
Asymmetric crying face association	Asymmetric crying face association	BEFREE	30260090		★☆☆☆☆ Found in Text Mining only
Atherosclerosis	Atherosclerosis	BEFREE	31030940, 31255737		★☆☆☆☆ Found in Text Mining only
Atherosclerosis	Atherosclerosis	Pubtator	32329448	Associate	★☆☆☆☆ Found in Text Mining only
B-Cell Lymphomas	B-Cell Lymphoma	BEFREE	26780985		★☆☆☆☆ Found in Text Mining only
Bladder Neoplasm	Bladder Neoplasm	BEFREE	28554751		★☆☆☆☆ Found in Text Mining only
Carcinoma	Carcinoma	BEFREE	30515801		★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	25053419	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma of bladder	Bladder carcinoma	BEFREE	28554751		★☆☆☆☆ Found in Text Mining only
Cardiovascular Diseases	Cardiovascular Diseases	BEFREE	30323875		★☆☆☆☆ Found in Text Mining only
Colitis	Colitis	BEFREE	19560465		★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	BEFREE	30249393		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	20348951, 23029137	Associate	★☆☆☆☆ Found in Text Mining only
Conventional (Clear Cell) Renal Cell Carcinoma	Renal Carcinoma	BEFREE	26780985		★☆☆☆☆ Found in Text Mining only
Degenerative polyarthritis	Arthritis	BEFREE	17599731, 29444976, 29457374		★☆☆☆☆ Found in Text Mining only
Desmoplastic Small Round Cell Tumor	Desmoplastic small round cell tumor	Pubtator	25010205	Associate	★☆☆☆☆ Found in Text Mining only
Diabetes	Diabetes	BEFREE	21858169		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus	Diabetes Mellitus	BEFREE	21858169		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus	Diabetes mellitus	Pubtator	36978091	Associate	★☆☆☆☆ Found in Text Mining only
Diabetic Nephropathies	Diabetic neuropathy	Pubtator	36978091	Inhibit	★☆☆☆☆ Found in Text Mining only
Diffuse Large B-Cell Lymphoma	Diffuse Lymphoma	BEFREE	27911272		★☆☆☆☆ Found in Text Mining only
Dystonia 3, Torsion, X-Linked	Dystonia	BEFREE	9341872		★☆☆☆☆ Found in Text Mining only
Epilepsy	Epilepsy	BEFREE	28963932		★☆☆☆☆ Found in Text Mining only
Epilepsy	Epilepsy	Pubtator	28963932	Inhibit	★☆☆☆☆ Found in Text Mining only
Glycosuria Renal	Renal glycosuria	Pubtator	36978091	Associate	★☆☆☆☆ Found in Text Mining only
Hematologic Neoplasms	Hematologic Neoplasms	BEFREE	15492844		★☆☆☆☆ Found in Text Mining only
Hepatitis B	Hepatitis b	Pubtator	32228643, 35695580	Associate	★☆☆☆☆ Found in Text Mining only
Hepatitis B Chronic	Hepatitis b	Pubtator	35695580	Associate	★☆☆☆☆ Found in Text Mining only
Huntington Disease	Huntington Disease	BEFREE	28973411		★☆☆☆☆ Found in Text Mining only
Huntington Disease	Huntington disease	Pubtator	28973411	Stimulate	★☆☆☆☆ Found in Text Mining only
Hypoxia	Hypoxia	Pubtator	12761217	Inhibit	★☆☆☆☆ Found in Text Mining only
Hypoxia	Hypoxia	Pubtator	23696831	Associate	★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory Bowel Disease	BEFREE	19560465		★☆☆☆☆ Found in Text Mining only
Inflammatory Bowel Diseases	Inflammatory bowel disease	Pubtator	32410873	Associate	★☆☆☆☆ Found in Text Mining only
Kidney Neoplasms	Kidney neoplasm	Pubtator	34907995	Associate	★☆☆☆☆ Found in Text Mining only
Leukemia, Myelocytic, Acute	Leukemia	BEFREE	21562049, 9010221		★☆☆☆☆ Found in Text Mining only
Liver carcinoma	Liver carcinoma	BEFREE	31802891		★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus, Systemic	Lupus Erythematosus	BEFREE	17873969		★☆☆☆☆ Found in Text Mining only
Lymphatic Metastasis	Lymphatic metastasis	Pubtator	24935588	Associate	★☆☆☆☆ Found in Text Mining only
Lymphoma	Lymphoma	BEFREE	27911272		★☆☆☆☆ Found in Text Mining only
Lymphoma	Lymphoma	Pubtator	27911272	Associate	★☆☆☆☆ Found in Text Mining only
Machado-Joseph Disease	Machado-Joseph Disease	BEFREE	21536589		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of gastrointestinal tract	Malignant gastrointestinal tract tumors	BEFREE	26780985		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of liver	Liver Cancer	BEFREE	28769986		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	BEFREE	24983969, 28986382		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of stomach	Stomach Neoplasms	BEFREE	24886657		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of urinary bladder	Urinary bladder cancer	BEFREE	28554751		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	18794148, 25753202, 29719213, 30515801, 31529218, 9010221		★☆☆☆☆ Found in Text Mining only
melanoma	Melanoma	BEFREE	20959475		★☆☆☆☆ Found in Text Mining only
Myocardial Infarction	Myocardial Infarction	BEFREE	26438688, 31708788		★☆☆☆☆ Found in Text Mining only
Nasopharyngeal carcinoma	Nasopharyngeal Carcinoma	BEFREE	30610793		★☆☆☆☆ Found in Text Mining only
Nasopharyngeal Carcinoma	Nasopharyngeal carcinoma	Pubtator	30610793	Associate	★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	15688030, 24886657, 24935588, 26780985, 27911272, 28963932, 29719213, 30323875		★☆☆☆☆ Found in Text Mining only
Non-Small Cell Lung Carcinoma	Lung carcinoma	BEFREE	24935588, 27976702		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	Pubtator	24484739	Associate	★☆☆☆☆ Found in Text Mining only
Ovarian Failure, Premature	Ovarian Failure	BEFREE	22285440		★☆☆☆☆ Found in Text Mining only
Precursor Cell Lymphoblastic Leukemia Lymphoma	Lymphoblastic Leukemia	LHGDN	16215946		★☆☆☆☆ Found in Text Mining only
Premature Menopause	Premature Menopause	BEFREE	22285440		★☆☆☆☆ Found in Text Mining only
Premature Menopause	Premature Menopause	GENOMICS_ENGLAND_DG	22285440		★☆☆☆☆ Found in Text Mining only
Prostate carcinoma	Prostate cancer	BEFREE	24983969, 28986382		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	35650605	Associate	★☆☆☆☆ Found in Text Mining only
Refractory anemias	Anemia	BEFREE	30551491		★☆☆☆☆ Found in Text Mining only
Rheumatoid Arthritis	Rheumatoid arthritis	BEFREE	17599731, 17873969, 30551491		★☆☆☆☆ Found in Text Mining only
Sarcoma	Sarcoma	BEFREE	25007147		★☆☆☆☆ Found in Text Mining only
Seizures	Seizures	Pubtator	28963932	Inhibit	★☆☆☆☆ Found in Text Mining only
Stomach Carcinoma	Stomach Carcinoma	BEFREE	24886657		★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	27027443, 30551491	Associate	★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	33103284	Inhibit	★☆☆☆☆ Found in Text Mining only
Triple Negative Breast Neoplasms	Triple Negative Breast Neoplasms	BEFREE	29588373		★☆☆☆☆ Found in Text Mining only
Uterine Cervical Neoplasms	Uterine neoplasm	Pubtator	26715362	Associate	★☆☆☆☆ Found in Text Mining only
Vitamin A Deficiency	Vitamin A Deficiency	BEFREE	31044535		★☆☆☆☆ Found in Text Mining only