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FLASH GENE
Symbol FOXP3 contributors: mct - updated : 03-07-2017
HGNC name forkhead box P3
HGNC id 6106
Corresponding disease
IPEX immunodysregulation, polyendocrinopathy, enteropathy
Location Xp11.23      Physical location : 49.106.897 - 49.121.288
Synonym name
  • scurfin
  • JM2 protein
  • FOXP3delta7
  • immunodeficiency, polyendocrinopathy, enteropathy, X-linked
    • Synonym symbol(s) PIDX, JM2, DIETER, SCURFIN, XPID, FXP3, AIID, MGC141961, MGC141963
    DNA
    TYPE functioning gene
    STRUCTURE 14.39 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • DNA binding protein
  • FKH binding sequences adjacent to critical NFAT regulatory site
  • proximal FOXP3 promoter transactivation was inhibited by FOXP3 and the SP transcription factor family member SP3
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 splicing 2397 47.1 431 - 2006 17005002
    isoform a
    11 splicing 2292 43.2 396 - 2006 17005002
  • lacking an in frame segment in the coding region
  • isoform b
    		•
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymph node    
     spleen   highly
     thymus   highly
    Visualeye    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immuneactivated B lymphocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a forkhead (FH, winged helix) domain with two loops-wings on the C terminal side of helix-turn-helix homeodomain
  • leucine zipper dimerization domain
  • a Treg-specific demethylated region (TSDR), a conserved, CpG-rich region within the FOXP3 locus
  • winged helix domain
    • HOMOLOGY
    interspecies homolog to murine Foxp3 (86.9pc)
    homolog to rattus Foxp3 (86.5pc)
    intraspecies homolog to FOXP2
    Homologene
    FAMILY
  • forkhead (winged-helix) family of transcriptional regulator
    • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • control switch for T cell activation and repressor of transcription (control of regulatory T cell development)
  • playing a critical role in the control of immune response
  • playing an indispensable role for the development and function of CD4(+)CD25(+) regulatory T cells
  • acting as a repressor of transcription and being both an essential and sufficient regulator of the development and function of regulatory T cells
  • SKP2 transcriptional repressor
  • unique marker of regulatory T cells and plays a crucial role in the development and function of those cells
  • key transcription factor for the development and suppressive activity of Treg (Regulatory T) cells
  • could induce gene silencing by inhibiting NFkappaB activity and by causing its target loci to adopt an inactive chromatin configuration
  • key determinant of cell fate in TP53-dependent DNA damage responses
  • is indispensible for the differentiation and function of regulatory T cells (T(reg) cells)
  • hypoxia is an intrinsic molecular cue that promotes FOXP3 expression, in turn eliciting potent anti-inflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability
  • in a late cellular differentiation process FOXP3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape
  • plays an important role not only as a master gene in T-regulatory cells, but also as a tumor suppressor
  • lineage-specification factor, executing its multiple activities mostly through transcriptional regulation of target genes
  • during inflammation, steady FOXP3 expression in Tregs is essential for maintaining their lineage identity and suppressive function
    • CELLULAR PROCESS cell life, differentiation
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS immunity/defense
    PATHWAY
    metabolism
    signaling
    a component
  • determining the number and functionality of peripheral T cells
    • INTERACTION
    DNA binding
    RNA
    small molecule metal binding,
  • Zn2+
    • protein
  • interacting with HMOX1
  • interacting with histone acetyltransferase-deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9 (required for repression)
  • interacting with AML1 in natural T(R) cells
  • interacts with RORA, and this interaction inhibits transcriptional activation mediated by RORA
  • interacting with LATS2 (LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells)
  • REL and JUNB cooperatively regulate FOXP3 expression by modulating the chromatin architecture of FOXP3 promoter region
  • both FOXP3 and SIVA1 function as negative regulators of IL2 gene expression in Treg cells, via suppression of NFATC1 by FOXP3 and of NFKB1 by both FOXP3 and SIVA1
  • orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting KAT8 and causing displacement of KDM5B
  • HIF1A -dependent induction of FOXP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa
  • may interact with DNA in large part indirectly, through protein-protein interactions
  • FOXP3 bound gene loci with a decreased FOXO1 occupancy were significantly down-regulated in Treg cells in contrast to FOXP3 unbound genes or FOXP3 bound sites that have increased FOXO1
  • FOXP3 function as a positive activator of IL2RA
  • direct physical interaction between TRIB1 and FOXP3 in live cells
  • IKZF2 up-regulate expression of FOXP3 protein, whereas SATB1 is known to inhibit its expression (
  • CDK2 negatively regulates the stability and activity of FOXP3 and implicate CDK-coupled receptor signal transduction in the control of regulatory T cell function and stability
  • role for PARP1 in controlling the function of Tregs through modulation of the stable expression of FOXP3
  • MBD32 has a key role in promoting Treg-specific demethylation region (TSDR) demethylation, FOXP3 expression, and Treg-suppressive function
  • UXT is a cofactor of FOXP3 and an important player in Treg-cell function
  • promotes transcription in association with the locus-specific transcription factor STAT3
  • MECP2 is critical to sustain FOXP3 expression in Tregs during inflammation
  • CREBBP and EP300 cooperate with several key Treg transcription factors that act on the FOXP3 promoter to promote FOXP3 production
  • PDCD5 participates likely in immune regulation by promoting regulatory T cell function via the PDCD5-KAT5-FOXP3 pathway (
  • Vitamin C potentiates TET activity and acts through TET2/TET3 to increase the stability of FOXP3 expression in TGFB1-induced T reg cells
    • cell & other
    REGULATION
    induced by PAEP (induction of FOXP3 expression by PAEP is accompanied by down regulation of the PI3K-MTOR signaling pathway)
    repressed by PIM1 that negatively regulates FOXP3 chromatin binding activity by specifically phosphorylating FOXP3 at Ser(422)
    Phosphorylated by LCK (LCK phosphorylated Tyr-342 of FOXP3)
    Other in the context of tumor suppression, is regulated in a TP53-dependent manner
    ASSOCIATED DISORDERS
    corresponding disease(s) IPEX
    Susceptibility to type 1 diabetes (IDDM)
    Variant & Polymorphism other increasing the risk of IDDM
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • dysruption of FOXp3, scurfin results in the fatal lymphoproliferative disorder of the scurfy mouse