Affinage

WT1

Wilms tumor protein · UniProt P19544

Round 2 corrected
Length
449 aa
Mass
49.2 kDa
Annotated
2026-04-28
130 papers in source corpus 40 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WT1 is a zinc finger transcription factor that governs urogenital development, hematopoietic differentiation, and epicardial morphogenesis by binding GC/TC-rich promoter elements to repress or activate context-dependent target genes. Four major isoforms arising from alternative splicing of exon 5 (±17AA) and the KTS insertion between zinc fingers 3 and 4 confer distinct functions: the −KTS isoform drives canonical DNA-binding–dependent transcriptional regulation of targets such as PDGF-A, Pax-2, EGFR, amphiregulin, E-cadherin, and CMIP (PMID:1332065, PMID:7720589, PMID:10490105, PMID:27650733), while the +KTS isoform regulates Sry expression and gonadal sex determination (PMID:19549635); the 17AA+ isoform suppresses apoptosis through the intrinsic mitochondrial pathway by repressing Bak (PMID:16518414). WT1 recruits chromatin-modifying co-factors—including the BASP1–prohibitin–HDAC1 repressor complex and the DNA demethylase TET2—to target promoters, dynamically reprogramming chromatin during podocyte injury and repair (PMID:19050011, PMID:24166496, PMID:25601757, PMID:32754639). Germline WT1 mutations cause Denys-Drash syndrome and other disorders of sex development, and somatic WT1 loss cooperates with oncogenic lesions such as FLT3-ITD to drive acute myeloid leukemia (PMID:1655284, PMID:30064973).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1990 High

    Positional cloning of the 11p13 Wilms tumor locus identified WT1 as a zinc finger gene with restricted kidney and hematopoietic expression, establishing it as a candidate transcriptional regulator and tumor suppressor.

    Evidence cDNA isolation, Northern blot, and sequence analysis of the 11p13 region

    PMID:2154335 PMID:2154702

    Open questions at the time
    • No direct transcriptional activity demonstrated
    • No target genes identified
    • No loss-of-function phenotype yet shown
  2. 1991 High

    Characterization of WT1 exon–intron structure revealed four conserved splice isoforms (±17AA, ±KTS), raising the question of whether these isoforms have distinct functions, while germline zinc finger mutations in Denys-Drash patients proved WT1 is essential for urogenital development.

    Evidence RNase protection, genomic cloning of splice variants; exon sequencing of DDS patients

    PMID:1654525 PMID:1655284 PMID:1658787

    Open questions at the time
    • Isoform-specific functions not yet dissected
    • Mechanism by which zinc finger mutations cause disease unknown
  3. 1992 High

    Demonstration that WT1 directly binds and represses the PDGF-A chain promoter established its biochemical activity as a sequence-specific transcriptional repressor of growth factor genes.

    Evidence Gel-shift, DNase I footprinting, and transient transfection reporter assays

    PMID:1332065

    Open questions at the time
    • Whether WT1 also activates transcription not yet tested
    • In vivo relevance of PDGF-A repression not confirmed
  4. 1993 High

    Physical interaction with p53 and the finding that WT1 can switch between repressor and activator modes—depending on p53 availability and point mutations in the transactivation domain—revealed WT1 as a context-dependent transcriptional regulator rather than a simple repressor.

    Evidence Co-immunoprecipitation, reporter assays with wild-type and mutant WT1

    PMID:8389468 PMID:8402654

    Open questions at the time
    • Structural basis of WT1–p53 interaction unresolved
    • In vivo relevance of the repressor-to-activator switch unclear
  5. 1995 High

    Identification of multiple direct target genes—Pax-2 (repressed), EGFR (repressed, mediating WT1-induced apoptosis), and amphiregulin (activated)—and self-association of WT1 through its N-terminal domain expanded the repertoire of WT1 transcriptional functions and dominant-negative mechanisms, while the EWS-WT1 fusion was characterized in desmoplastic small round cell tumor.

    Evidence DNase I footprinting, inducible expression with EGFR rescue of apoptosis, oligonucleotide arrays, in vitro/in vivo binding assays, fusion transcript cloning

    PMID:7479946 PMID:7588596 PMID:7720589 PMID:7862627

    Open questions at the time
    • Genome-wide target repertoire unknown
    • Self-association stoichiometry and structural basis unresolved
  6. 1996 Medium

    Evidence that WT1 harbors an RNA recognition motif and co-immunoprecipitates with spliceosomal proteins suggested a post-transcriptional role, though this remained less well characterized than its transcriptional functions.

    Evidence Structural modeling, spliceosomal Co-IP, RNA degradation–localization experiment

    PMID:8589729

    Open questions at the time
    • No direct RNA-binding assay performed
    • No specific RNA targets identified
    • Functional consequence of spliceosomal association not demonstrated
  7. 1999 High

    Wt1-null mouse studies showed WT1 is required for epicardial and subepicardial mesenchymal cell development; YAC complementation fully rescued cardiac but only partially rescued urogenital defects, revealing tissue-specific regulatory requirements.

    Evidence Wt1 knockout mouse, LacZ YAC reporter, YAC rescue

    PMID:10101119

    Open questions at the time
    • Epicardial target genes not identified
    • Mechanism of tissue-specific rescue differences unknown
  8. 2002 High

    Gene-dosage experiments in mice established WT1 as a master regulator of podocyte identity, with reduced Wt1 levels causing glomerulonephritis or mesangial sclerosis and loss of podocyte-specific genes nphs1 and podocalyxin.

    Evidence Wt1 heterozygous knockout and inducible transgenic mice

    PMID:11912180

    Open questions at the time
    • Direct versus indirect regulation of nphs1 and podocalyxin not distinguished
    • Chromatin-level mechanism not explored
  9. 2006 High

    Isoform-specific studies resolved that 17AA+ WT1 suppresses apoptosis via the intrinsic mitochondrial pathway by repressing Bak, while hnRNP-U was identified as a direct zinc-finger–dependent interaction partner modulating WT1 transcriptional activation.

    Evidence Isoform-specific siRNA, caspase and mitochondrial assays; endogenous Co-IP and domain mapping

    PMID:16518414 PMID:16924231

    Open questions at the time
    • Full set of 17AA+-specific targets not defined
    • In vivo role of hnRNP-U–WT1 interaction untested
  10. 2008 Medium

    Discovery of the BASP1 co-repressor complex on WT1 target promoters during podocyte differentiation provided the first chromatin-level mechanism for WT1-mediated gene repression, with sumoylation dynamically regulating BASP1 recruitment.

    Evidence ChIP in differentiating podocytes, BASP1 sumoylation analysis

    PMID:19050011

    Open questions at the time
    • Genome-wide extent of BASP1 co-occupancy unknown
    • Whether sumoylation is necessary in vivo untested
  11. 2009 High

    The +KTS isoform was shown to cell-autonomously regulate Sry expression, with its loss causing male-to-female sex reversal rescued by exogenous FGF9, mechanistically linking alternative splicing to gonadal sex determination.

    Evidence Wt1(+KTS)-specific knockout mice, immunofluorescence, ex vivo gonad culture rescue

    PMID:19549635

    Open questions at the time
    • Whether +KTS acts via transcriptional or post-transcriptional mechanisms on Sry unresolved
    • Direct binding to Sry locus not demonstrated
  12. 2013 Medium

    The WT1-BASP1-prohibitin repressor complex was shown to recruit BRG1 and HDAC1 while displacing CBP from target promoters, and WT1 was found to repress epicardial chemokines Ccl5/Cxcl10 to promote heart morphogenesis, broadening the chromatin-remodeling and developmental scope of WT1 function.

    Evidence Co-IP, ChIP, reporter assays; Wt1-KO epicardial transcriptome with functional chemokine assays

    PMID:23900076 PMID:24166496

    Open questions at the time
    • Whether prohibitin-BRG1 recruitment is universal across WT1 targets unknown
    • Direct WT1 binding at chemokine promoters not confirmed
  13. 2015 High

    WT1 was found to recruit the DNA demethylase TET2 to target genes—with AML-derived TET2 mutations disrupting this interaction—and to regulate mitotic fidelity through MAD2 interaction and APC/C inhibition, revealing non-transcriptional roles and linking WT1/TET2 to a shared leukemogenic pathway.

    Evidence Co-IP, ChIP, colony formation, AML mutation exclusivity analysis; MAD2 interaction and APC/C ubiquitination assays

    PMID:25601757 PMID:25789599

    Open questions at the time
    • Genome-wide WT1-TET2 co-occupancy map not generated
    • In vivo significance of WT1-MAD2 interaction not confirmed in animal models
  14. 2016 High

    WT1 directly represses CMIP via two response elements in podocytes, and genetic epistasis between Wt1 and Osr1 in kidney development further defined the transcription factor network governing nephron progenitor maintenance.

    Evidence ChIP, EMSA, luciferase reporter, WT1 siRNA; CRISPR-labeled Osr1-Wt1 double-heterozygous mice

    PMID:27442016 PMID:27650733

    Open questions at the time
    • Whether CMIP derepression is sufficient to cause glomerular disease not tested
    • Molecular basis of Osr1-Wt1 interaction not defined
  15. 2018 High

    Conditional Wt1 deletion in podocytes revealed Notch1 pathway activation and HES1-mediated EMT as a downstream disease mechanism amenable to pharmacological rescue, while Wt1 haploinsufficiency was shown to cooperate with Flt3-ITD to drive AML, establishing Wt1 as a bona fide leukemia tumor suppressor gene in vivo.

    Evidence Tamoxifen-inducible podocyte Wt1 deletion with Notch inhibitor rescue; Wt1-het × Flt3-ITD mouse leukemia model

    PMID:29398135 PMID:30064973

    Open questions at the time
    • Whether Notch pathway activation is the primary mediator versus a bystander in podocyte injury unknown
    • Epigenetic versus genetic mechanisms of Wt1-haploinsufficiency-driven leukemogenesis not dissected
  16. 2020 High

    Genome-wide ChIP-seq demonstrated that WT1 binds nearly all genes essential for the glomerular filtration barrier and undergoes dynamic chromatin reprogramming during podocyte injury and repair, while ZF4 mutations were shown to sequester β-catenin and cause 46,XX testicular DSD.

    Evidence ChIP-seq in murine podocytes and human kidney organoids; exome sequencing, Co-IP, and Wt1-XX mouse gonad analysis

    PMID:32493750 PMID:32754639

    Open questions at the time
    • Causal hierarchy of WT1 chromatin changes versus injury signals not resolved
    • Whether β-catenin sequestration is the sole mechanism of ZF4-mediated sex reversal untested
  17. 2021 High

    PRMT5-mediated methylation of hnRNPA1 was shown to facilitate IRES-dependent translation of Wt1 mRNA, establishing a post-transcriptional layer of WT1 regulation essential for granulosa cell function and follicle development.

    Evidence Conditional Prmt5 knockout in granulosa cells, hnRNPA1 methylation analysis, Wt1 overexpression rescue

    PMID:34448450

    Open questions at the time
    • Whether IRES-dependent translation is relevant outside granulosa cells unknown
    • Structural basis of hnRNPA1-WT1 IRES interaction not defined
  18. 2022 High

    Autophagy-mediated degradation of WT1 protein was identified as a mechanism controlling granulosa cell differentiation, adding a protein-turnover layer to WT1 regulation.

    Evidence ATG5/BECN1 siRNA and chloroquine-mediated autophagy inhibition with WT1 accumulation and differentiation assays

    PMID:35025698

    Open questions at the time
    • Autophagy receptor or ubiquitin signal targeting WT1 for degradation not identified
    • Whether autophagy-mediated WT1 turnover operates in podocytes or other WT1-dependent lineages unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of WT1 isoform-specific DNA versus RNA recognition, the genome-wide co-occupancy maps for WT1 with TET2 and the BASP1-prohibitin complex across cell types, and whether the mitotic checkpoint role of WT1 via MAD2 contributes to tumor suppression in vivo.
  • No crystal structure of full-length WT1 or isoform-specific complexes
  • Comprehensive WT1 interactome across developmental contexts not available
  • In vivo relevance of WT1-MAD2 axis in tumorigenesis untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-1266738 Developmental Biology 6 R-HSA-4839726 Chromatin organization 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
BASP1CTNNB1HNRNPULIMS1MAD2L1OSR1TET2TP53
Complex memberships
WT1-BASP1-prohibitin repressor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 WT1 was isolated as a zinc finger polypeptide gene at chromosome 11p13, with expression restricted predominantly to kidney and hematopoietic cells, and predicted to function as a transcriptional regulator based on its four zinc finger domains and proline/glutamine-rich region. Positional cloning, cDNA isolation, Northern blot expression analysis Cell High 2154335 2154702
1991 WT1 gene consists of 10 exons generating four alternatively spliced transcripts: two splice sites produce isoforms with/without a 17-amino-acid insertion (exon 5) and with/without 3 amino acids (KTS) between zinc fingers 3 and 4, with the relative ratios conserved between normal tissue and Wilms tumors. RNase protection analysis, genomic and cDNA cloning Proceedings of the National Academy of Sciences of the United States of America High 1658787
1991 Germline point mutations in WT1 zinc finger domains (exons 8 and 9) cause Denys-Drash syndrome, with these mutations directly affecting DNA sequence recognition, demonstrating WT1's essential role in urogenital development. Exon sequencing, functional analysis of zinc finger mutations Cell High 1655284
1991 Constitutional mutations in WT1 zinc finger domains contribute to abnormal genital system development, establishing WT1 as essential for both kidney and gonadal development. Constitutional mutation analysis of WT1 coding exons Nature High 1654525
1991 Mouse WT1 protein is greater than 95% conserved with human WT1, with developmental expression in fetal kidney peaking just before birth and declining postpartum, consistent with a role as a negative regulator of nephroblast growth. Murine Wt1 cDNA isolation, developmental Northern blot expression analysis Molecular and cellular biology High 1671709
1992 WT1 protein functions as a transcriptional repressor of the PDGF-A chain promoter by binding to multiple sites in the PDGF-A promoter, as demonstrated by gel-shift analysis and DNase I footprinting, achieving >50-fold repression. Gel-shift analysis, DNase I footprinting, transient transfection reporter assays Proceedings of the National Academy of Sciences of the United States of America High 1332065
1993 WT1 physically associates with p53 in transfected cells, modulating their transcriptional activity: in the absence of p53, WT1 acts as a transcriptional activator of the EGR1 site, and WT1 cooperatively enhances p53 transactivation of the muscle creatine kinase promoter. Co-immunoprecipitation in transfected cells, transcriptional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 8389468
1993 WT1 protein is exclusively nuclear, localizing to podocytes during mesonephric and metanephric development and persisting in adult podocytes, supporting its role as a transcription factor during urogenital development and adult kidney homeostasis. Immunohistochemistry, immunofluorescence, confocal laser microscopy, in situ hybridization Development (Cambridge, England) High 8306891
1993 A point mutation in WT1 converting glycine to aspartic acid in the putative trans-activation domain converts the protein from a transcriptional repressor to an activator of its target DNA sequence, providing the 'second hit' mechanism in WAGR-associated Wilms tumorigenesis. Mutant WT1 functional analysis in transfection reporter assays Cancer research Medium 8402654
1995 WT1 induces apoptosis in osteosarcoma cell lines via an inducible system, mediating transcriptional repression of the EGFR promoter at two TC-rich repeat sequences and reducing EGFR synthesis; constitutive EGFR expression rescued WT1-induced apoptosis. Tetracycline-inducible WT1 expression, EGFR promoter reporter assays, apoptosis assays, EGFR rescue experiment The EMBO journal High 7588596
1995 WT1 directly represses Pax-2 transcription by binding to three high-affinity sites in the 5' untranslated Pax-2 leader sequence (demonstrated by DNase I footprinting), coinciding with down-regulation of Pax-2 during glomerular precursor differentiation in vivo. DNase I footprinting, co-transfection reporter assays, immunofluorescence in mouse kidney sections Development (Cambridge, England) High 7720589
1995 WT1 can self-associate in vitro and in vivo through its amino-terminal domain, and mutant WT1 proteins impaired in DNA recognition can antagonize WT1-mediated transcriptional repression through these oligomeric interactions. In vitro binding assays, co-immunoprecipitation in vivo, transcriptional repression assays Proceedings of the National Academy of Sciences of the United States of America High 7479946
1995 GATA-1 transactivates the WT1 hematopoietic-specific 3' enhancer by binding to a GATA-binding site, as demonstrated by gel shift competition experiments and transactivation assays, linking GATA-1 to regulation of WT1 expression in hematopoiesis. Gel shift competition assays, transactivation reporter assays, RT-PCR co-expression analysis The Journal of biological chemistry Medium 7890725
1996 WT1 was found by structural modeling to contain an N-terminal RNA recognition motif (RRM) similar to the splicing factor U1A, and WT1 co-immunoprecipitates with spliceosomal proteins, with nuclear RNA degradation abolishing the speckled WT1 localization pattern. Structural modeling, co-immunoprecipitation with spliceosomal proteins, RNA degradation experiment Nature genetics Medium 8589729
1996 WT1 (both isoforms WT1 and WT1+KTS) represses transcription of the novH (nov) promoter through intact zinc finger regions and the NH2 transcription repression domain, with constitutive WT1 expression decreasing endogenous NOVH protein levels in 293 cells. Transient co-transfection reporter assays, in vitro footprinting, Western blot of NOVH protein Oncogene Medium 8622864
1998 Constitutive WT1 expression in the myeloid progenitor cell line 32D cl3 blocked G-CSF-induced differentiation and instead promoted proliferation, accompanied by constitutive activation of both Stat3α and Stat3β downstream of G-CSF receptor signaling. Retroviral WT1 transduction of 32D cl3 cells, differentiation assay, Western blot of Stat3 activation Blood Medium 9531608
1999 WT1(-KTS) isoform directly binds to the amphiregulin promoter and potently activates its transcription; amphiregulin, an EGF family member, mirrors WT1 expression during fetal kidney development and stimulates epithelial branching in embryonic kidney organ cultures. High-density oligonucleotide array after inducible WT1 expression, promoter binding assays, organ culture branching assay Cell High 10490105
1999 Wt1 is required for development of the epicardium and subepicardial mesenchymal cells, and is expressed in the proepicardium; Wt1-null embryos show severe epicardial defects and absence of SEMCs leading to embryonic lethality; a human WT1 YAC rescues heart defects completely but only partially rescues urogenital defects. LacZ reporter YAC, Wt1 knockout mouse analysis, YAC complementation Development (Cambridge, England) High 10101119
2000 WT1 directly activates E-cadherin transcription by binding to a conserved GC-rich EGR1-like site in the E-cadherin promoter; stable WT1 expression in NIH 3T3 fibroblasts induces epithelial differentiation features including E-cadherin upregulation. Retroviral WT1 expression, transient transfection reporter assays, in vitro binding with nuclear extracts, dominant-negative WT1 block The Journal of biological chemistry High 10753894
2002 WT1 is a key regulator of podocyte function: reduced WT1 levels in mice result in crescentic glomerulonephritis or mesangial sclerosis depending on gene dosage, with downstream podocyte-specific genes nphs1 and podocalyxin dramatically downregulated. Wt1 knockout and inducible YAC transgenic mouse models, gene expression analysis Human molecular genetics High 11912180
2006 The 17AA(+) WT1 isoforms exert antiapoptotic functions in leukemia cells by acting upstream of mitochondria in the intrinsic apoptosis pathway; 17AA(+)WT1-specific siRNA activates caspase-3 and -9 and Bax, while constitutive 17AA(+)WT1 expression protects mitochondrial membrane integrity and decreases proapoptotic Bak expression. The zinc-finger DNA-binding region is essential for these antiapoptotic functions. Isoform-specific siRNA knockdown, constitutive expression, caspase activation assays, mitochondrial membrane assays, Western blot for Bak/Bax Oncogene High 16518414
2006 hnRNP-U directly interacts with WT1 endogenously without requiring other proteins or nucleic acids; the interaction involves the zinc fingers of WT1 and the middle domain of hnRNP-U, and hnRNP-U modulates WT1 transcriptional activation of a bona fide WT1 target gene. Co-immunoprecipitation of endogenous proteins, domain-mapping pulldown assays, transcriptional reporter assays Oncogene Medium 16924231
2008 Brain Acid Soluble Protein 1 (BASP1) acts as a transcriptional cosuppressor blocking WT1 transcriptional activation; during podocyte differentiation, WT1 and BASP1 co-occupy the Bak, c-myc, and podocalyxin promoters, and BASP1 promoter occupancy is dynamically regulated by sumoylation of BASP1. Chromatin immunoprecipitation (ChIP), podocyte differentiation assay, BASP1 sumoylation analysis Nucleic acids research Medium 19050011
2009 WT1(+KTS) isoform cell-autonomously regulates Sry expression in the gonad; XY mice lacking WT1(+KTS) show reduced SRY protein per cell, decreased SRY-expressing cells, blocked Sertoli cell differentiation (loss of SOX9 and Fgf9), and male-to-female sex reversal; addition of recombinant FGF9 to ex vivo gonad cultures rescues the Sertoli cell differentiation defect. Wt1(+KTS)-null mouse model, immunofluorescence, ex vivo gonad culture with recombinant FGF9 rescue Human molecular genetics High 19549635
2013 Prohibitin is part of the WT1-BASP1 transcriptional repression complex; prohibitin interacts with BASP1, is recruited to WT1 target gene promoters in a BASP1-dependent manner, and cooperates with BASP1 to recruit the chromatin remodeling factor BRG1 and displace CBP from promoters; this complex also recruits PIP2 and HDAC1 to WT1 target genes. Co-immunoprecipitation, ChIP, promoter reporter assays, nuclear colocalization Oncogene Medium 24166496
2013 WT1 is required to repress expression of inhibitory chemokines Ccl5 and Cxcl10 in epicardial cells, partly directly and partly by increasing IRF7 levels; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation, linking WT1 to heart morphogenesis via chemokine regulation. Transcriptome analysis of Wt1-KO epicardial cells, functional chemokine assays (migration, proliferation), expression correlation Human molecular genetics Medium 23900076
2011 PINCH1 interacts with WT1 in podocyte nuclei after TGF-β1-induced nuclear translocation; the interaction is mediated by the LIM1 domain of PINCH1 and the C-terminal zinc-finger domain of WT1, and PINCH1-WT1 interaction suppresses WT1-mediated podocalyxin expression. Co-immunoprecipitation, pulldown assays, promoter-luciferase reporter, nuclear translocation imaging PloS one Medium 21390327
2015 WT1 physically interacts with and recruits TET2 to WT1 target genes to activate their expression and suppress leukemia cell proliferation; multiple AML-derived TET2 mutations disrupt the WT1-TET2 interaction; WT1 and TET2 are mutated in a mutually exclusive manner in AML, suggesting a shared IDH1/2-TET2-WT1 pathway. Co-immunoprecipitation, ChIP, colony formation assay, AML mutation analysis Molecular cell High 25601757
2015 WT1 regulates the fidelity of chromosome segregation through interaction with the spindle assembly checkpoint protein MAD2; WT1 delays anaphase entry by inhibiting the ubiquitination activity of the Anaphase Promoting Complex/Cyclosome (APC/C), establishing a role for WT1 in mitotic checkpoint control and genomic stability. WT1-MAD2 interaction assays, APC/C ubiquitination assay, chromosome segregation analysis Cell cycle (Georgetown, Tex.) Medium 25789599
2018 Wt1 haploinsufficiency enhances hematopoietic stem cell self-renewal in an age-dependent manner and cooperates with Flt3-ITD mutation to induce fully penetrant AML, demonstrating that Wt1 loss contributes to leukemogenesis through progressive genetic and epigenetic alterations. Wt1 heterozygous knockout mouse model, stem cell functional assays, genetic cooperation with Flt3-ITD Blood Medium 30064973
2018 Loss of Wt1 in mature podocytes activates Notch1 signaling (upregulation of Notch1 and Nrarp), represses FoxC2, and upregulates Hey2 and HES1; HES1 induction is associated with upregulation of epithelial-mesenchymal transition genes and mediates podocyte EMT; pharmacological inhibition of Notch signaling ameliorates glomerular scarring in Wt1-deleted mice. Tamoxifen-inducible Cre-LoxP Wt1 deletion, immunofluorescence, Notch inhibitor rescue experiment Kidney international High 29398135
2020 WT1 undergoes highly dynamic changes in binding to target genes during podocyte injury and repair, affecting chromatin state and expression of target genes; WT1 binds nearly all genes crucial for maintenance of the glomerular filtration barrier and mediates epigenetic transcriptional reprogramming during injury. ChIP-seq in murine podocytes and human kidney organoids, transcriptome analysis during injury/repair Science advances High 32754639
2020 Heterozygous WT1 variants affecting zinc finger 4 (ZF4) cause 46,XX testicular/ovotesticular DSD; ZF4 mutant proteins physically interact with and sequester β-CATENIN, leading to upregulation of testis-specific pathways and masculinization of XX gonads. Exome sequencing, co-immunoprecipitation, human granulosa cell line transfection, Wt1-XX mouse gonad phenotyping Proceedings of the National Academy of Sciences of the United States of America High 32493750
2021 PRMT5 facilitates IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1; loss of Prmt5 in granulosa cells dramatically reduces WT1 protein expression, arrests follicle development, and derepresses steroidogenic gene expression, which is rescued by Wt1 overexpression. Conditional Prmt5 knockout in granulosa cells, mechanistic studies of HnRNPA1 methylation, Wt1 overexpression rescue eLife High 34448450
2022 Autophagy regulates granulosa cell differentiation by degrading WT1 protein; disruption of autophagy (via ATG5/BECN1 siRNA or chloroquine) causes WT1 accumulation, which inhibits GC differentiation (suppressing CYP19A1/Aromatase and FSHR expression and estradiol synthesis). siRNA knockdown of ATG5/BECN1, pharmacological autophagy inhibition, WT1 protein accumulation assay, co-immunoprecipitation Autophagy High 35025698
1995 EWS-WT1 chimeric transcripts result from a t(11;22)(p13;q12) translocation fusing EWS exons 1–7 to WT1 exons 8–10 (the last three zinc fingers), generating a predicted transcriptional modulator at WT1 target sites that underlies desmoplastic small round cell tumor. Genomic DNA fusion breakpoint isolation and sequencing, chimeric transcript RT-PCR analysis Proceedings of the National Academy of Sciences of the United States of America High 7862627
2016 Osr1 interacts with Wt1 in the developing kidney (demonstrated by CRISPR-labeled endogenous proteins); mice heterozygous for both Osr1 and Wt1 null alleles show synergistic kidney development defects including agenesis and hypoplasia, with reduced nephron progenitor cells and decreased Gdnf expression, demonstrating genetic epistasis between these two factors. CRISPR protein labeling, double heterozygous mouse model, nephron progenitor cell counting, Gdnf expression analysis PloS one Medium 27442016
2016 WT1 is a major repressor of the CMIP gene in podocytes by directly binding to two WT1 response elements in the human CMIP proximal promoter (at -290/-274 and -57/-41); WT1 silencing promotes Cmip expression, and Cmip is early and significantly increased in podocytes with primary Wt1 defects (Denys-Drash and Frasier syndromes). ChIP assay, EMSA, luciferase reporter assay, decoy oligonucleotide competition, WT1 siRNA knockdown Kidney international High 27650733
2017 CUG-translated WT1 (cugWT1), an N-terminally extended isoform, functions as an oncogene promoting cell transformation and activating c-myc, bcl-2, and egfr expression; AKT phosphorylates cugWT1 on Ser62 to protect it from FBXW8-mediated proteasomal degradation. In contrast, AUG-WT1 acts as a tumor suppressor and represses the same target genes by recruiting HDAC1 and inhibiting cugWT1 function. CUG vs AUG translation start site analysis, AKT phosphorylation assay, FBXW8 ubiquitination assay, colony formation assay, target gene reporter assays Carcinogenesis Medium 29040381

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
1990 Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1805 2154335
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1990 Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 1267 2154702
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1991 Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 795 1655284
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1991 Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proceedings of the National Academy of Sciences of the United States of America 605 1658787
2004 Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proceedings of the National Academy of Sciences of the United States of America 457 15365188
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1991 WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 430 1654525
1999 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development (Cambridge, England) 425 10101119
2007 A tumor suppressor and oncogene: the WT1 story. Leukemia 397 17361230
2009 Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 372 19752335
1992 Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 329 1317488
1993 Physical and functional interaction between WT1 and p53 proteins. Proceedings of the National Academy of Sciences of the United States of America 322 8389468
2007 Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 315 17371932
1995 WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. The EMBO journal 308 7588596
1997 Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 298 9028964
2006 The many facets of the Wilms' tumour gene, WT1. Human molecular genetics 290 16987884
1993 Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development (Cambridge, England) 284 8306891
1997 A clinical overview of WT1 gene mutations. Human mutation 281 9090524
2001 WT1 proteins: functions in growth and differentiation. Gene 274 11595161
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
1995 Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proceedings of the National Academy of Sciences of the United States of America 249 7862627
2008 Brain-derived neurotrophic factor and obesity in the WAGR syndrome. The New England journal of medicine 246 18753648
2015 WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Molecular cell 245 25601757
1991 Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development. Molecular and cellular biology 242 1671709
1999 The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 238 10490105
1995 Repression of Pax-2 by WT1 during normal kidney development. Development (Cambridge, England) 233 7720589
1992 Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. Proceedings of the National Academy of Sciences of the United States of America 227 1332065
2002 WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Human molecular genetics 225 11912180
2001 Wilms tumor and the WT1 gene. Experimental cell research 224 11237525
1993 The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 221 8393820
2002 CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 219 12200377
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