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FLASH GENE
Symbol FOXO4 contributors: mct - updated : 11-02-2010
HGNC name forkhead box O4
HGNC id 7139
Location Xq13.1      Physical location : 70.315.998 - 70.323.384
Synonym name
  • AF-X1 protein
  • myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila); translocated to, 7
  • fork head domain transcription factor AFX1
  • Synonym symbol(s) AFX1, MLLT7, AFX, MGC120490
    DNA
    TYPE functioning gene
    STRUCTURE 7.36 kb     3 Exon(s)
    MAPPING cloned Y linked N status confirmed
    Map cen - DXS1111 - DXS339 - DXS1275 - DLG3 - DXS453 - ARR3 - DXS348 - FOXO4 -IL2RG - GJB1 - NONO - ZNF261 - TAF1 - DXS7502 - DXS559 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 - 3365 53.5 505 - 2002 11779849
    isoform 1
    - splicing 3200 - 450 liver,kidney, pancreas 2002 11779849
    isoform Zeta
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus    
    Cardiovascularheart    
    Digestiveliver    
    Endocrinepancreas    
     thyroid   highly
    Nervousbrain    
     nervecranial nerve  highly
    Reproductivefemale systemplacenta  highly
    Respiratorylung    
     respiratory tractlarynx  highly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousoptic nerve
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    cell cycle     cell cycle, interphase, G1
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a forkhead (FH, winged helix) domain
  • two loops-wings on the C-terminal side of helix-turn-helix homeo domain
  • HOMOLOGY
    interspecies homolog to Drosophila trithorax
    ortholog to C.elegans Daf-16
    homolog to rattus Foxo4 (88.5pc)
    homolog to murine Foxo4 (88.7pc)
    Homologene
    FAMILY
  • O class of winged helix/forkhead transcription factor family
  • CATEGORY regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • upon oxidative stress, ATXN3 and FOXO4 translocate to the nucleus
  • basic FUNCTION
  • playing a role in the insulin signaling pathway
  • down regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes
  • involved in negative regulation of the cell cycle
  • play an important role in a variety of processes, such as cell cycle arrest, cell death, tumor suppression, metabolism, and protection from oxidative stress
  • may be involved in folliculogenesis and luteinization
  • transcription factor playing an important role in cell survival in response to oxidative stress
  • mediator of autophagy, having the ability to induce cell cycle arrest, DNA repair and apoptosis
  • SP1, NFYC and FOXO3, FOXO4 transcription factors are involved in the regulation of STK11 transcription
  • FOXO4 interacts with SREBF2 and EPAS1 to modulate CYP51A1 promoter activity
  • role for FOXO4 in the regulation of CYP51A1 expression
  • CELLULAR PROCESS cell cycle, checkpoint
    cell life, proliferation/growth
    nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    text cell cycle arrest negative control of proliferation
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
  • binding
  • binding to IREs and can activate transcription of IGFBP1
  • RNA
    small molecule
    protein
  • upregulating RBL2 expression
  • interacting with CDKN1B for cycle arrest and induction of apoptosis
  • bindingn YWHAZ through its DNA-binding domain
  • CTNNB1
  • interacting with CBP, MYOCD, SIRT1, SRF
  • ATXN3 interacts with the forkhead box O (FOXO) transcription factor FOXO4 and activates the FOXO4-dependent transcription of the manganese superoxide dismutase (SOD2) gene
  • in the nucleus, concomitantly bind to the SOD2 gene promoter and increase the expression of the antioxidant enzyme SOD2
  • cell & other
    REGULATION
    activated by
  • FOXO3 and possibly by other FOXO factors in a positive feedback loop, which is disrupted by growth factors (Essaghir 2009)
  • inhibited by
  • acetylation or phosphorylation
  • repressed by
  • USP7
  • Other
  • acetylated upon peroxide stress and deacetylated by the longevity protein SIRT1
  • O-glcNacylation enhances FOXO4 transcriptional regulation in response to stress
  • dephosphoryaltion triggers nuclear translocation
  • ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion      
    with HRX(ALL1) in acute lymphocytic leukemia with translocation t(X;11)(q13;q23)
    constitutional       dominant negative
    isoform zeta suppresses the FOXO4alpha stimulation of BCL6 promoter and inhibits tumor cell apoptosis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
  • a constitutively active mutant where phosphorylation sites Thr32, Ser187 and Ser262 have been mutated to lalanine may have therapeutic potential in ERBB2/HER2-overexpressing cancers as it inhibits ERBB2-mediated cell survival, transformation and tumorigenicity
  • ANIMAL & CELL MODELS