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FLASH GENE
Symbol WT1 contributors: mct/pgu - updated : 31-01-2017
HGNC name Wilms tumor 1
HGNC id 12796
DNA
TYPE functioning gene
SPECIAL FEATURE
text WIT1 overlapping 5' - WT1
STRUCTURE 47.76 kb     10 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site
text structure several potential binding sites for ETV4 (activation of the WT1promoter) ; antisens regulatory region (WT1 ARR) contains a transcriptional silencer element acting on AWT1 and WT1-As imprinted transcripts
MAPPING cloned Y linked N status confirmed
RNA
TRANSCRIPTS type messenger
text four variants generated by alternative splicing of exon 5 and the KTS sequence between zinc fingers 3 and 4 in exon 9, other alternative isoforms with different initiation sites
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
9 - 2978 54.4 500 - 2003 12665546
  • also called variant C
  • lacking exon 5 but containing the KTS sequence at the end of exon 9
  • initiation of translation like variant A
    • 9 splicing 2969 54.1 497 - 2003 12665546
  • also called varaiant A
  • lacking exon 5 and the sequence encoding KTS at the end of exon 9
  • initiating translation from a non-AUG (CUG) site and also from a downstream in frame AUG
    • 10 splicing 3020 55.8 514 - 2003 12665546
  • also called variant B
  • deletion of 3 AA, contains all ten exons but does not contain the additional sequence added to exon 9
  • initiation of translation like variant A
    • 10 splicing 2480 - 302 less abundant 2010 20591825
  • exon 5 /- KTS
  • deletion of 20 AA
  • acts mainly as a transcriptional factor, binding GC-rich DNA sequences with a high affinity
  • specific interaction with ZNF224
    • 9 - 2438 33 288 in renal and hematopoietic cells, maternally imprinting in the kidney 2004 14681303
  • also called AWT1
  • a new 5' exon in intron 1
    • 10 - 3029 56.1 517 - 2010 20591825
  • also called variant D, + KTS
  • contains ten exon and the additional sequence coding for KTS at the end of exon 9
  • translation initiation like variant A
  • displays little affinity for DNA
  • present in nuclear domains rich in splicing factors and has been found associated with snRNPs
    		•
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart     Mus musculusFetal
    Digestivesalivary gland    
    Reproductivefemale systemovary   
     female systemuterus   
     male systemtestis    Homo sapiensFetal
    Urinarykidneynephronrenal capsule   Homo sapiensAdult
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone   
    Epithelialbarrier liningmesothelium   Homo sapiensFetal
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    ReproductiveSertoli cell Homo sapiensFetal
    Urinarypodocyte Homo sapiensAdult
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text
  • highly, in developing kidney, located in condensing mesenchyme
  • in the developing kidney, with CXXC5 are coexpressed in podocytes of maturing nephrons
  • specifically expressed in Sertoli cells in the developing testis
    • IMPRINTING maternally, paternally
    text sometimes paternally imprinted in placenta and fetal brain, but maternally imprinted in fibroblasts and lymphocytes
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal transactivation domain proline endoglutamic rich
  • four C terminal zinc fingers (C2H2 type)
  • a KTS motif between ZF3 and ZF4
  • nuclear translocation of WT1 involves KPNA2, KPNB1 and a NLS in the third zinc finger
    • HOMOLOGY
    interspecies homolog to murine Wt1 (97.5pc)
    homolog to rattus Wt1 (97.1pc)
    Homologene
    FAMILY
  • EGR C2H2-type zinc-finger protein family
    • CATEGORY regulatory , transcription factor , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    intracellular,nucleus,nucleolus
    text
  • nuclear diffuse (-Kts), speckles (+Kts)
  • shuttles between the nucleus and cytoplasm
  • undergoing nucleocytoplasmic shuttling, and cytoplasmic WT1 was higher in malignant than in normal cells
    • basic FUNCTION
  • first considered as a repressor but appearing now as a transcriptional activator of specific genes i.e AMH and implicated in gonadal differentiation
  • contributing to breast cancer progression by promoting breast cancer cell proliferation
  • zinc finger protein playing a role in urogenital development and occurrence of glomerulosclerosis (regulation of podocyte function)
  • may have an important role in tumorigenesis of various types of bone and soft-tissue sarcomas
  • required for SOX9 expression and maintenance of tubular architecture in the developing testis
  • may be an important component of the nitric oxide-dependent regulation of T lymphocyte proliferation and potential function
  • crucial role in the generation of mesenchymal cardiovascular progenitor cells in the epicardium and during embryonic stem cell differentiation, through direct regulation of the SNAI1 transcription factor and E-cadherin
  • activates CXXC5 transcription through the upstream enhancer region
  • negatively regulates WNT/beta-catenin pathway via its target gene CXXC5
  • novel immune regulatory function of WT1 in controlling IL10 gene expression
  • WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics
  • critically regulates epicardial RA signalling via direct activation of the ALDH1A2 gene
  • role for WT1 in the regulation of morphogen receptors involved in the proliferation, migration, and differentiation of epicardial and epicardially-derived cells
  • exerts an important, yet previously unappreciated function in regulating H3K27 histone modifications and repressing gene expression
  • regulates epicardial EMT and heart development through canonical WNT, non-canonical WNT, and retinoic acid signaling pathways
  • main role in the regulation of the process of Mesenchimal-Epithelial-Transition and in the development and maturation of podocytes
  • in prostate cancer WT1 may function as a novel oncogene facilitating development of the lethal metastatic phenotype
  • implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies
  • is a regulator of the mitotic checkpoint and chromosomal stability
  • central role of WT1 in podocyte differentiation
    • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text normal kidney differentiation, hemapoietic progenitor cells ; involved in nephrogenesis
    PATHWAY
    metabolism
    signaling
  • role of CITED2 during sex determination through a WT1/NR5A1 regulatory pathway
  • biological function of menin-WT1 regulated PAX2 signaling in endocrine neoplasia and renal disease
    • a component
    INTERACTION
    DNA binding to both GC-rich and TC repeat elements that are present in multiple promoters
    RNA
    small molecule
    protein
  • regulating for SRY in the sex determination pathway
  • interacting with CITED2, NR5A1
  • HTRA2 is a WT1 binding partner that cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs
  • transcriptional activator of the immunosuppressant cytokine interleukin-10 (IL10)
  • BASP1 is a WT1 cofactor that suppresses the transcriptional activation function of WT1
  • ALDH1A2 is a direct transcriptional target of WT1 in epicardial cells
  • MEN1 specifically interact with WT1 (WT1 is a specific cofactor for menin-dependent and PcG-mediated H3K27 trimethylation and DNA hypermethylation for gene silencing)
  • LIMS1 interacted with WT1, a nuclear transcription factor that is essential for regulating podocyte-specific gene expression in adult kidney
  • VEGFA is a direct, bona fide WT1 target gene in sarcoma and WT1 plays a key role in optimizing the response of tumor cells to hypoxia
  • bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding site
  • SOX11 represents a synergistic factor for WT1 in regulating the WNT4 gene expression that is critical for nephrogenesis during kidney ontogeny
  • NR2F2 directly regulates the expression of both EYA1 and WT1 in the metanephric mesenchyme
  • BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor
  • USP18 is a transcriptional target of WT1, suggesting that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis
  • maintains testicular cord integrity by regulating the expression of COL4A1 and COL4A2
  • ZNF224, is a novel WT1-associating protein that enhances the transcriptional activation of the human vitamin D receptor promoter by WT1
  • WT1 regulates the mitotic checkpoint complex (MCC) by directly interacting with the spindle assembly checkpoint protein, MAD2L1
  • NR4A1 protects pancreatic beta-cells against H2O2 mediated apoptosis by up-regulating WT1 expression
    • cell & other
  • promoting quiescence of the CD34(+), CD38(-), stem cell population
    • REGULATION
    inhibited by phosphorylation by PKA, resulting in its translocation from nucleus to cytosol
    Other regulated by EP300 (increased the expression of endogenous WT1 mRNA and promoted the activation of the WT1 promoter and intronic enhancer)
    ASSOCIATED DISORDERS
    corresponding disease(s) DDS , FS , IDMS , GUD , WAGR , SRN4 , NPHS4
    related resource Wilms Tumour database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in myelodysplastic syndrome in progression and in acute leukemia
    constitutional     --low  
    in glomerulonephritis or mesanglial scelerosis
    tumoral   translocation    
    with EWSR1 t(11;22) (p13;q12) in desmoplastic round-cell tumor
    constitutional germinal mutation      
    in renal failure
    tumoral     --over  
    in breast cancer with poor prognosis
    constitutional germinal mutation      
    in exons 8 and 9 in steroid-resistant nephrotic syndrome
    tumoral       loss of function
    in WILMS tumor
    constitutional        
    association with congenital diaphragmatic hernia (see DDS)
    tumoral     --over  
    in pediatric acute myeloid leukemia but does not predict survival
    constitutional     --low  
    in Sertoli cells results in the downregulation of the important basal lamina component, which in turn, causes the breakdown of the basal lamina and subsequent testicular cord disruption
    Susceptibility
  • to Wilms tumor
  • susceptibility to tuberculosis
    • Variant & Polymorphism SNP
  • rs2057178 SNP associated with susceptibility to tuberculosis
    • Candidate gene
    Marker EPS8, as ABCB1 and WT1, may be a clinically valuable biomarker for assessing the outcome of acute lymphoblastic leukemia (ALL) patients
    Therapy target
    ANIMAL & CELL MODELS
    mouse strains lacking KTS+isoform, showing a complex XY sex reversal due to a drastic reduction of Sry expression pattern