Disease relevance of WT1

• To test its functional properties, we developed osteosarcoma cell lines expressing WT1 under an inducible tetracycline-regulated promoter [1].
• The Wilms' tumor suppressor protein WT1 is a transcriptional regulator that plays a key role in the development of the kidneys [2].
• WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis [3].
• HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria [4].
• WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY [5].
• Further study is needed to determine whether clinical conditions exhibiting tissue remodeling, such as asthma and/or chronic obstructive pulmonary disease, demonstrate reduced levels of WT1 or its repressor activity [6].

Psychiatry related information on WT1

• Wilms' tumor suppressor (WT1) is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease [7].
• Fluorescence in situ hybridization (FISH) with biotin-labeled probes mapping to 11p13 has been used for the molecular analysis of deletions of the WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) locus [8].
• In the ovary, SF-1 and WT1 transcripts persist in the gonadal ridge from the earliest developmental stages throughout the critical period of sex determination [9].
• This disease complex may be confused with bilateral Wilms tumor, which may alter therapeutic decision-making [10].
• We describe two patients with Wilms tumor and one with acute lymphoblastic leukemia, who developed severe veno-occlusive disease of the liver according to the Baltimore criteria while undergoing chemotherapy; the symptoms were hepatomegaly, ascites, hyperbilirubinemia, weight gain and, in one patient, short-term lethargy [11].

High impact information on WT1

• WT1 encodes a zinc finger transcription factor implicated in kidney differentiation and tumorigenesis [12].
• Here, we show that WT1 -KTS isoforms associate and synergize with SF-1 to promote MIS expression [13].
• Products of steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1) genes are essential for mammalian gonadogenesis prior to sexual differentiation [13].
• In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1 [13].
• We propose that WT1 and Dax-1 functionally oppose each other in testis development by modulating SF-1-mediated transactivation [13].

Chemical compound and disease context of WT1

• Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome [14].
• Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression [15].
• We describe here the changes in the expression and DNA binding activity of the WT1 gene product in P19 embryonal carcinoma cells and embryonic stem cells triggered to differentiate by either retinoic acid (RA) or DMSO [16].
• But when the proliferation of breast cancer cells was inhibited by tamoxifen or all-trans retinoic acid (ATRA), WT1 protein expression decreased [17].
• When the proliferation of breast cancer cells was stimulated by 17beta-estradiol, WT1 protein expression increased [17].

Biological context of WT1

• The Wilms tumor suppressor gene WT1 encodes a developmentally regulated transcription factor that is mutated in a subset of embryonal tumors [1].
• Induction of WT1 resulted in programmed cell death [1].
• This effect, which was differentially mediated by the alternative splicing variants of WT1, was independent of p53 [1].
• The activity of WT1 varied significantly depending on the presence or absence of an alternatively spliced region located upstream of the zinc finger domain [18].
• We now demonstrate that p53, the product of a tumor-suppressor gene with ubiquitous expression, physically associates with WT1 in transfected cells [19].

Anatomical context of WT1

• WT1 is expressed in the podocytes throughout life, but its function in this cell type is unknown [3].
• The Wilms' tumor 1 (WT1) and sex-determining region of the Y chromosome (SRY) genes are essential for development of the mammalian gonads and mutations in these genes are associated with gonadal dysgenesis in humans [5].
• The Wilms tumour 1 (WT1) gene is believed to contribute to the growth and differentiation of certain tissues, including mesothelium [20].
• Moreover, WT1 levels in endometriotic stromal cells are significantly down-regulated compared with normal endometrial stromal cells [21].
• The WT1 is an essential factor for activation of the Mis promoter; therefore, the persistence of the mullerian duct in patients with Denys-Drash syndrome may result from deregulation of the MIS gene [22].

Associations of WT1 with chemical compounds

• In contrast, WT1 exerts a cooperative effect on p53, enhancing its ability to transactivate the muscle creatine kinase promoter [19].
• BASP1 is present in the developing nephron structures of the embryonic kidney and, coincident with that of WT1, its expression is restricted to the highly specialized podocyte cells of the adult kidney [2].
• Glutathione S-transferase pulldown assays and far Western blots revealed that zinc fingers VI-X (amino acids 231-370) are required for interaction with the zinc finger region of WT1 [23].
• WT1 activates a glomerular-specific enhancer identified from the human nephrin gene [24].
• In vivo down-regulation of WT1 in endometriotic stromal cells (vs. normal endometrial stromal cells) may in part be responsible for aberrantly increased P450arom expression and estrogen formation in this pathological tissue [21].

Physical interactions of WT1

• WT1 encodes a transcription factor which binds to the EGR1 consensus sequence, mediating transcriptional repression [19].
• Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites [5].
• The WT1 Wilms' tumor suppressor gene product interacts with estrogen receptor-alpha and regulates IGF-I receptor gene transcription in breast cancer cells [25].
• WT1 has been shown in vitro to interact with the promoter of the MDR1, a gene involved in the multidrug resistance phenomenon [26].
• Interestingly a mutation associated with DDS enhanced both -KTS WT1 binding to U2AF65 and splicing-factor colocalization [27].

Regulatory relationships of WT1

• WT1 splice variants lacking a KTS insert between zinc fingers 3 and 4 suppressed IGF-IR promoter activity in the absence of p53 or in the presence of wild-type p53 [28].
• Functionally, BMZF2 inhibits transcriptional activation by WT1 [23].
• PODXL is also transcriptionally regulated by WT1 and has roles in cell adhesion and anti-adhesion [29].
• To examine the potential interplay between WT1 and ERalpha in control of IGF-IR gene transcription we employed ER-depleted C4 cells that were generated by clonal selection of ER-positive MCF-7 cells that were maintained in estrogen-free conditions [25].
• Taken together, our results show that BASP1 is a WT1-associated factor that can regulate WT1 transcriptional activity [2].

Other interactions of WT1

• In the absence of p53, WT1 acts as a potent transcriptional activator of the early growth response gene 1 (EGR1) site, rather than a transcriptional repressor [19].
• The mother, who has aniridia, was also found to carry a deletion including both the aniridia candidate gene (AN2) and the Wilms tumor predisposition gene (WT1) [8].
• BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1 [2].
• To clarify aspects of immune mechanisms and proliferation of PNH cells, we investigated HLA-DRB1, -DQA1, and -DQB1 alleles by polymerase chain reaction (PCR)-based genotyping and expression of the Wilms' tumor gene, WT1, by real-time reverse transcriptase-PCR (RT-PCR) in 21 PNH and 21 aplastic anemia (AA) patients [4].
• Inhibition of Wilms tumor 1 transactivation by bone marrow zinc finger 2, a novel transcriptional repressor [23].

Analytical, diagnostic and therapeutic context of WT1

• Microinjection of the WT1 cDNA into quiescent cells or cells in early to mid G1 phase blocked serum-induced cell cycle progression into S phase [18].
• RT-PCR analysis showed that the mean values of WT1 RNA were 3413, 712, and 334 copies/microg RNA in PNH, AA, and healthy individuals, respectively [4].
• Co-immunoprecipitation experiments are consistent with an in vivo association between WT1 and BMZF2 [23].
• Electrophoretic mobility shift assays showed strong binding by recombinant WT1(-)KTS protein and weaker or no binding by the WT1(+)KTS protein to DNA probes containing WT1 binding sites from these three promoters [30].
• We suggest that the molecular techniques used here (heterozygosity testing for polymorphic markers mapping between AN2 and WT1 and deletion analysis by dosage, cytogenetic analysis, or in situ hybridization) can be employed to identify sporadic aniridia patients with and without increased tumor risk [31].

References