FOXO3 (forkhead box O3)

Gene

• Entrez ID: 2309
• Gene name: Forkhead box O3
• Gene symbol: FOXO3
• Synonyms: AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A
• Chromosome: 6
• Chromosome location: 6q21
• Summary: This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000433	hsa-miR-222-3p	qRT-PCR, ChIP, Luciferase reporter assay, Western blot, Northern blot	20388878
MIRT000434	hsa-miR-221-3p	qRT-PCR, ChIP, Luciferase reporter assay, Western blot, Northern blot	20388878
MIRT000671	hsa-miR-182-5p	Luciferase reporter assay, Western blot	19188590
MIRT000671	hsa-miR-182-5p	Luciferase reporter assay	23262295
MIRT004198	hsa-miR-197-3p	Microarray	16822819
MIRT004198	hsa-miR-197-3p	Microarray, qRT-PCR, Western blot	26540468
MIRT004495	hsa-miR-155-5p	qRT-PCR, Luciferase reporter assay, Western blot	20371610
MIRT004495	hsa-miR-155-5p	Flow, Immunoblot, Immunofluorescence, Immunohistochemistry, Microarray, qRT-PCR, Western blot	21304824
MIRT004495	hsa-miR-155-5p	Proteomics	19650740
MIRT004495	hsa-miR-155-5p	Luciferase reporter assay, qRT-PCR, Western blot	23970205
MIRT004495	hsa-miR-155-5p	qRT-PCR	23250986
MIRT004495	hsa-miR-155-5p	Luciferase reporter assay	27091996
MIRT004495	hsa-miR-155-5p	Luciferase reporter assay	28006785
MIRT004495	hsa-miR-155-5p	Luciferase reporter assay	28401267
MIRT005450	hsa-miR-96-5p	Luciferase reporter assay, qRT-PCR, Western blot	21203424
MIRT005450	hsa-miR-96-5p	Luciferase reporter assay, qRT-PCR, Western blot	25369914
MIRT006284	hsa-miR-23a-3p	Immunoblot, Luciferase reporter assay, qRT-PCR	22084234
MIRT006284	hsa-miR-23a-3p	Immunoblot, Luciferase reporter assay, qRT-PCR	22095742
MIRT007326	hsa-miR-9-5p	Luciferase reporter assay	23509296
MIRT017201	hsa-miR-335-5p	Microarray	18185580
MIRT037525	hsa-miR-744-5p	CLASH	23622248
MIRT039975	hsa-miR-615-3p	CLASH	23622248
MIRT050180	hsa-miR-26a-5p	CLASH	23622248
MIRT051735	hsa-let-7c-5p	CLASH	23622248
MIRT053249	hsa-miR-126-3p	In situ hybridization, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	23603512
MIRT054878	hsa-miR-29a-3p	Luciferase reporter assay, qRT-PCR, Western blot	24467486
MIRT217307	hsa-miR-21-5p	PAR-CLIP	20371350
MIRT217309	hsa-miR-590-5p	PAR-CLIP	20371350
MIRT217310	hsa-miR-548c-3p	PAR-CLIP	20371350
MIRT217321	hsa-miR-126-5p	PAR-CLIP	21572407
MIRT217321	hsa-miR-126-5p	PAR-CLIP	20371350
MIRT217322	hsa-miR-340-5p	PAR-CLIP	21572407
MIRT217322	hsa-miR-340-5p	PAR-CLIP	20371350
MIRT217323	hsa-miR-621	PAR-CLIP	21572407
MIRT217323	hsa-miR-621	PAR-CLIP	20371350
MIRT315203	hsa-miR-4714-3p	PAR-CLIP	20371350
MIRT315219	hsa-miR-4795-5p	PAR-CLIP	21572407
MIRT315219	hsa-miR-4795-5p	PAR-CLIP	20371350
MIRT315221	hsa-miR-217	Luciferase reporter assay, Western blot, qRT_PCR	24376725
MIRT315226	hsa-miR-548av-3p	PAR-CLIP	20371350
MIRT409788	hsa-miR-671-5p	PAR-CLIP	20371350
MIRT409789	hsa-miR-3622a-3p	PAR-CLIP	20371350
MIRT409790	hsa-miR-3622b-3p	PAR-CLIP	20371350
MIRT409792	hsa-miR-4786-3p	PAR-CLIP	20371350
MIRT409793	hsa-miR-6079	PAR-CLIP	20371350
MIRT438227	hsa-miR-223-3p	Luciferase reporter assay	24324762
MIRT440613	hsa-miR-218-5p	HITS-CLIP	23212916
MIRT544595	hsa-miR-4795-3p	PAR-CLIP	21572407
MIRT544595	hsa-miR-4795-3p	PAR-CLIP	20371350
MIRT544596	hsa-miR-6069	PAR-CLIP	21572407
MIRT544596	hsa-miR-6069	PAR-CLIP	20371350
MIRT544597	hsa-miR-665	PAR-CLIP	21572407
MIRT544598	hsa-miR-5590-3p	PAR-CLIP	21572407
MIRT544598	hsa-miR-5590-3p	PAR-CLIP	20371350
MIRT544599	hsa-miR-142-5p	PAR-CLIP	21572407
MIRT544599	hsa-miR-142-5p	PAR-CLIP	20371350
MIRT544600	hsa-miR-1179	PAR-CLIP	21572407
MIRT544600	hsa-miR-1179	PAR-CLIP	20371350
MIRT562327	hsa-miR-6828-5p	PAR-CLIP	20371350
MIRT562328	hsa-miR-1228-3p	PAR-CLIP	20371350
MIRT562329	hsa-miR-6882-5p	PAR-CLIP	20371350
MIRT563750	hsa-miR-4328	PAR-CLIP	20371350
MIRT563751	hsa-miR-4275	PAR-CLIP	20371350
MIRT563752	hsa-miR-100-3p	PAR-CLIP	20371350
MIRT658089	hsa-miR-3927-5p	HITS-CLIP	23824327
MIRT658090	hsa-miR-6832-3p	HITS-CLIP	23824327
MIRT668263	hsa-miR-498	HITS-CLIP	23824327
MIRT668264	hsa-miR-4279	HITS-CLIP	23824327
MIRT668265	hsa-miR-525-5p	HITS-CLIP	23824327
MIRT668266	hsa-miR-520a-5p	HITS-CLIP	23824327
MIRT668267	hsa-miR-1976	HITS-CLIP	23824327
MIRT668268	hsa-miR-3653-5p	HITS-CLIP	23824327
MIRT668269	hsa-miR-6747-3p	HITS-CLIP	23824327
MIRT668270	hsa-miR-6727-3p	HITS-CLIP	23824327
MIRT668271	hsa-miR-4722-3p	HITS-CLIP	23824327
MIRT677034	hsa-miR-5089-5p	HITS-CLIP	23824327
MIRT677035	hsa-miR-23b-5p	HITS-CLIP	23824327
MIRT677036	hsa-miR-23a-5p	HITS-CLIP	23824327
MIRT677037	hsa-miR-6506-5p	HITS-CLIP	23824327
MIRT677038	hsa-miR-619-5p	HITS-CLIP	23824327
MIRT733196	hsa-miR-592	Luciferase reporter assay	26629010
MIRT734600	hsa-miR-31-5p	ELISA, Immunofluorescence, Immunohistochemistry, Luciferase reporter assay, Microarray, qRT-PCR, Western blot	27541266
MIRT735009	hsa-miR-93-5p	Luciferase reporter assay	25823655
MIRT735311	hsa-miR-30c-5p	In situ hybridization, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	26080425

Transcription factors

Transcription factor	Regulation	Reference
ABL1	Activation	15509806
NFKB1	Unknown	19299143
RELA	Unknown	19299143
SIRT1	Repression	17558024;21841822
SIRT3	Unknown	23665396
TP53	Unknown	19299143
TSC22D3	Repression	20018851

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IDA	20371612
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IMP	18787191
GO:0000785	Component	Chromatin	ISA
GO:0000976	Function	Transcription regulatory region sequence-specific DNA binding	ISS
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA	21873635
GO:0000978	Function	RNA polymerase II cis-regulatory region sequence-specific DNA binding	ISS
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	IBA	21873635
GO:0000981	Function	DNA-binding transcription factor activity, RNA polymerase II-specific	ISA
GO:0001227	Function	DNA-binding transcription repressor activity, RNA polymerase II-specific	IDA	20371612
GO:0001228	Function	DNA-binding transcription activator activity, RNA polymerase II-specific	ISS
GO:0003677	Function	DNA binding	IDA	21329882
GO:0003700	Function	DNA-binding transcription factor activity	IDA	14734530
GO:0005515	Function	Protein binding	IPI	10102273, 11864996, 14976264, 15084259, 15084260, 15126506, 16809346, 18312651, 18393360, 18593906, 20181828, 21532621, 21621563, 21909281, 22761832, 23283301, 25241761, 25609649, 28514442, 29445193
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	10102273, 15084260, 16751106, 21329882, 22761832, 23283301, 23640897, 25327288
GO:0005634	Component	Nucleus	IMP	29445193
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IDA	10102273, 15084260, 16751106, 20371612, 21329882, 23283301
GO:0005739	Component	Mitochondrion	IDA	23283301
GO:0005741	Component	Mitochondrial outer membrane	IDA	29445193
GO:0005759	Component	Mitochondrial matrix	IBA	21873635
GO:0005759	Component	Mitochondrial matrix	IDA	29445193
GO:0005829	Component	Cytosol	IDA	23640897
GO:0005829	Component	Cytosol	TAS
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IBA	21873635
GO:0006357	Process	Regulation of transcription by RNA polymerase II	ISS
GO:0006390	Process	Mitochondrial transcription	IMP	29445193
GO:0006417	Process	Regulation of translation	IDA	21329882
GO:0006915	Process	Apoptotic process	IEA
GO:0008013	Function	Beta-catenin binding	IPI	15905404
GO:0010508	Process	Positive regulation of autophagy	ISS
GO:0014737	Process	Positive regulation of muscle atrophy	ISS
GO:0019221	Process	Cytokine-mediated signaling pathway	TAS
GO:0019901	Function	Protein kinase binding	IPI	16751106, 18593906, 21329882
GO:0030336	Process	Negative regulation of cell migration	IMP	19188590
GO:0031490	Function	Chromatin DNA binding	ISS
GO:0032991	Component	Protein-containing complex	IDA	23283301, 29445193
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	IMP	15084260
GO:0034246	Function	Mitochondrial transcription factor activity	IMP	29445193
GO:0034599	Process	Cellular response to oxidative stress	ISS
GO:0042149	Process	Cellular response to glucose starvation	IDA	29445193
GO:0042594	Process	Response to starvation	ISS
GO:0043065	Process	Positive regulation of apoptotic process	IDA	20371612
GO:0043525	Process	Positive regulation of neuron apoptotic process	IMP	10102273
GO:0043565	Function	Sequence-specific DNA binding	IDA	10102273
GO:0045648	Process	Positive regulation of erythrocyte differentiation	IDA	14734530
GO:0045893	Process	Positive regulation of transcription, DNA-templated	IDA	10102273, 15084260
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	10102273, 14734530
GO:0070542	Process	Response to fatty acid	ISS
GO:1902895	Process	Positive regulation of pri-miRNA transcription by RNA polymerase II	ISS
GO:1990837	Function	Sequence-specific double-stranded DNA binding	IDA	28473536

Other IDs

• MIM: 602681
• HGNC: 3821
• e!Ensembl: ENSG00000118689

Protein

• UniProt ID: O43524
• Protein name: Forkhead box protein O3 (AF6q21 protein) (Forkhead in rhabdomyosarcoma-like 1)
• Protein function: Transcriptional activator that recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3' and regulates different processes, such as apoptosis and autophagy (PubMed:10102273, PubMed:16751106, PubMed:21329882). Acts as a positive regulator of autophagy in skeletal muscle: in starved cells, enters the nucleus following dephosphorylation and binds the promoters of autophagy genes, such as GABARAP1L, MAP1LC3B and ATG12, thereby activating their expression, resulting in proteolysis of skeletal muscle proteins (By similarity). Triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress (PubMed:10102273, PubMed:16751106). Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (PubMed:21329882). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription (PubMed:23283301). In response to metabolic stress, translocates into the mitochondria where it promotes mtDNA transcription. Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity).
• PDB: 2K86, 2LQH, 2LQI, 2UZK, 6MNL
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00250	Forkhead	157 → 244	Forkhead domain	Domain
  PF16675	FOXO_KIX_bdg	432 → 511	KIX-binding domain of forkhead box O, CR2	Family
  PF16676	FOXO-TAD	604 → 645	Transactivation domain of FOXO protein family	Domain

• Sequence:

  MAEAPASPAPLSPLEVELDPEFEPQSRPRSCTWPLQRPELQASPAKPSGETAADSMIPEE
  EDDEDDEDGGGRAGSAMAIGGGGGSGTLGSGLLLEDSARVLAPGGQDPGSGPATAAGGLS
  GGTQALLQPQQPLPPPQPGAAGGSGQPRKCSSRRNAWGNLSYADLITRAIESSPDKRLTL
  SQIYEWMVRCVPYFKDKGDSNSSAGWKNSIRHNLSLHSRFMRVQNEGTGKSSWWIINPDG
  GKSGKAPRRRAVSMDNSNKYTKSRGRAAKKKAALQTAPESADDSPSQLSKWPGSPTSRSS
  DELDAWTDFRSRTNSNASTVSGRLSPIMASTELDEVQDDDAPLSPMLYSSSASLSPSVSK
  PCTVELPRLTDMAGTMNLNDGLTENLMDDLLDNITLPPSQPSPTGGLMQRSSSFPYTTKG
  SGLGSPTSSFNSTVFGPSSLNSLRQSPMQTIQENKPATFSSMSHYGNQTLQDLLTSDSLS
  HSDVMMTQSDPLMSQASTAVSAQNSRRNVMLRNDPMMSFAAQPNQGSLVNQNLLHHQHQT
  QGALGGSRALSNSVSNMGLSESSSLGSAKHQQQSPVSQSMQTLSDSLSGSSLYSTSANLP
  VMGHEKFPSDLDLDMFNGSLECDMESIIRSELMDADGLDFNFDSLISTQNVVGLNVGNFT
  GAKQASSQSWVPG

• Sequence length: 673