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Earlier studies have revealed one function of the inhibitory mechanism of curcumin. Activating PKCα induces WT1 gene expression via signalling through downstream JNK and c-JUN. In the present study, the effect of c-JUN/AP-1 binding and transcriptional regulation of the WT1 gene promoter was investigated in K562 leukaemic cells. The non-cytotoxic dose (IC20 values) of curcumin (WT1 and AP-1 inhibitors) was employed to examine its effect on WT1 gene-mediated WT1 and AP-1 protein expression. Non-cytotoxic doses of both tanshinone IIA (AP-1 DNA-binding inhibitor) and SP600125 (JNK inhibitor) were used to test the role of c-JUN/AP-1 in WT1 gene expression. Curcumin, tanshinone IIA, and SP600125 inhibited WT1 protein expression in a dose-dependent manner (5-15 μM) at 24 h as shown by immunoblotting. A ChIP assay showed that curcumin and tanshinone IIA inhibited AP-1 and WT1 binding to the proximal WT1 promoter (-301 bp), and a luciferase reporter assay showed that the WT1 luciferase gene reporter activity was decreased after curcumin, tanshinone IIA, and SP600126 treatments. Furthermore, depletion of c-JUN abrogated WT1 gene expression. In summary, AP-1 contributes to the WT1 autoregulation of WT1 gene expression in leukaemic K562 cells.
The Wilms' tumor gene WT1 consists of 10 exons and encodes a zinc finger transcription factor. There are four major WT1 isoforms resulting from alternative splicing at two sites, exon 5 (17AA) and exon 9 (KTS). All major WT1 isoforms are overexpressed in leukemia and solid tumors and play oncogenic roles such as inhibition of apoptosis, and promotion of cell proliferation, migration and invasion. In the present study, a novel alternatively spliced WT1 isoform that had an extended exon 4 (designated as exon 4a) with an additional 153 bp (designated as 4a sequence) at the 3' end was identified and designated as an Ex4a(+)WT1 isoform. The insertion of exon 4a resulted in the introduction of premature translational stop codons in the reading frame in exon 4a and production of C-terminal truncated WT1 proteins lacking zinc finger DNA-binding domain. Overexpression of the truncated Ex4a(+)WT1 isoform inhibited the major WT1-mediated transcriptional activation of anti-apoptotic Bcl-xL gene promoter and induced mitochondrial damage and apoptosis. Conversely, suppression of the Ex4a(+)WT1 isoform by Ex4a-specific siRNA attenuated apoptosis. These results indicated that the Ex4a(+)WT1 isoform exerted dominant negative effects on anti-apoptotic function of major WT1 isoforms. Ex4a(+)WT1 isoform was endogenously expressed as a minor isoform in myeloid leukemia and solid tumor cells and increased regardless of decrease in major WT1 isoforms during apoptosis, suggesting the dominant negative effects on anti-apoptotic function of major WT1 isoforms. These results indicated that Ex4a(+)WT1 isoform had an important physiological function that regulated oncogenic function of major WT1 isoforms.
WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.
In immunotherapy by cancer antigen-derived peptide vaccine, vaccination of cytotoxic T lymphocyte (CTL) peptide alone is common, while it remains unclear whether the addition of helper peptide vaccine to the CTL peptide vaccine is of great advantage for the enhancement of tumor immunity. In the present study, combination vaccine of Wilms' tumor gene 1(WT1) protein-derived CTL and helper peptides induced the strong infiltration of WT1-specific CD8+ T cells into mouse tumor at frequencies of 8.8%, resulting in the formation of multiple microscopic necrotic lesions in the tumor, whereas the frequencies of WT1-specific CD8+ T cell infiltration into the tumor in the vaccination of the CTL peptide alone were only 0.32%. The majority of the infiltrated WT1-specific CD8+ T cells was effector phenotype T cells, but importantly, WT1-specific CD8+CD44+CD62L+CD103+ resident memory T cells, which could differentiate into a lot of effector phenotype T cells, existed in the tumor of mice vaccinated with the both WT1 peptides. Furthermore, T-cell receptor repertoire analysis showed the oligoclonality of these tumor infiltrating WT1 tetramer+ CD8+ T cells, and 3 clones occupied about half of them. These results indicated that WT1-specific CD4+ T cells played an essential role not only in the priming and activation of WT1-specific CD8+ T cells, but also in trafficking and infiltration of the CD8+ T cells into tumors. These results should provide us with the concept that in the clinical setting, combination vaccine of WT1-specific CTL and helper peptides would be more advantageous than the CTL peptide vaccine alone.
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
Glycoprotein 210 (GP210) is a transmembrane component of the nuclear pore complex of metazoans, with a short carboxyterminus protruding towards the cytoplasm. Its function is unknown, but it is considered to be a major structural component of metazoan nuclear pores. Yet, our previous findings showed pronounced differences in expression levels in embryonic mouse tissues and cell lines. In order to identify factors regulating GP210, the genomic organization of human GP210 was analyzed in silico.
This study aims to observe the differentiating effect of shikonin on Wilms' tumor 1 (WT1)-positive HL-60 cells and investigate the fate of the differentiated leukemia cells. WT1 overexpression unaffected cell viability but promoted resistance to H2O2-induced DNA injury and cell apoptosis. The binding of shikonin to the WT1 protein was confirmed by molecular docking and drug affinity reaction target stability (DARTS). Shikonin at the non-cytotoxic concentration could decrease the WT1 protein and simultaneously reduced the CD34 protein and increased the CD11b protein in a dose-dependent manner in normal HL-60 cells but not in WT1-overexpressed HL-60 cells. Shikonin unaffected HL-60 cell viability in 48 h. However, it lasted for 10 days; could attenuate cell proliferation, mitochondrial membrane potential (MMP), and self-renewal; prevent the cell cycle; promote cell apoptosis. In a mouse leukemia model, shikonin could decrease the WT1 protein to prevent leukemia development in a dose-dependent manner. In this study, we also confirmed preliminarily the protein-protein interactions between WT1 and CD34 in molecular docking and CO-IP assay. Our results suggest that: 1. shikonin can down-regulate the WT1 protein level for leukemia differentiation therapy, and 2. the interaction between WT1 and CD34 proteins may be responsible for granulocyte/monocyte immaturity in HL-60 cells.
The Wilms' tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, and fibroblasts. Expression of Wt1 in cardiomyocytes has been suggested but remained a controversial issue, as well as the role of Wt1 in cardiomyocyte development and regeneration after injury. We determined cardiac Wt1 expression during embryonic development, in the adult, and after cardiac injury by quantitative RT-PCR and immunohistochemistry. As in vitro model, phenotypic cardiomyocyte differentiation, i.e., the appearance of rhythmically beating clones from mouse embryonic stem cells (mESCs) and associated changes in gene expression were analyzed. We detected Wt1 in cardiomyocytes from embryonic day (E10.5), the first time point investigated, until adult age. Cardiac Wt1 mRNA levels decreased during embryonic development. In the adult, Wt1 was reactivated in cardiomyocytes 48 h and 3 weeks following myocardial infarction. Wt1 mRNA levels were increased in differentiating mESCs. Overexpression of Wt1(-KTS) and Wt1(+KTS) isoforms in ES cells reduced the fraction of phenotypically cardiomyocyte differentiated clones, which was preceded by a temporary increase in c-kit expression in Wt1(-KTS) transfected ES cell clones and induction of some cardiomyocyte markers. Taken together, Wt1 shows a dynamic expression pattern during cardiomyocyte differentiation and overexpression in ES cells reduces their phenotypical cardiomyocyte differentiation.
Wt1 encodes a zinc finger protein that is crucial for epicardium development. Although WT1 is also expressed in coronary endothelial cells (ECs), the abnormal heart development observed in Wt1 knockout mice is mainly attributed to its functions in the epicardium. Here, we have generated an inducible endothelial-specific Wt1 knockout mouse model (Wt1KOΔEC). Deletion of Wt1 in ECs during coronary plexus formation impaired coronary blood vessels and myocardium development. RNA-Seq analysis of coronary ECs from Wt1KOΔEC mice demonstrated that deletion of Wt1 exerted a major impact on the molecular signature of coronary ECs and modified the expression of several genes that are dynamically modulated over the course of coronary EC development. Many of these differentially expressed genes are involved in cell proliferation, migration and differentiation of coronary ECs; consequently, the aforementioned processes were affected in Wt1KOΔEC mice. The requirement of WT1 in coronary ECs goes beyond the initial formation of the coronary plexus, as its later deletion results in defects in coronary artery formation. Through the characterization of these Wt1KOΔEC mouse models, we show that the deletion of Wt1 in ECs disrupts physiological blood vessel formation.
The Wilms' tumour suppressor protein WT1 plays a central role in the development of the kidney and also other organs. WT1 can act as a transcription factor with highly context-specific activator and repressor functions. We previously identified Brain Acid Soluble Protein 1 (BASP1) as a transcriptional cosuppressor that can block the transcriptional activation function of WT1. WT1 and BASP1 are co-expressed during nephrogenesis and both proteins ultimately become restricted to the podocyte cells of the adult kidney. Here, we have analysed the WT1/BASP1 complex in a podocyte precursor cell line that can be induced to differentiate. Chromatin immunoprecipitation revealed that WT1 and BASP1 occupy the promoters of the Bak, c-myc and podocalyxin genes in podocyte precursor cells. During differentiation-dependent upregulation of podocalyxin expression BASP1 occupancy of the podocalyxin promoter is reduced compared to that of WT1. In contrast, the repressive WT1/BASP1 occupancy of the c-myc and Bak promoters is maintained and these genes are downregulated during the differentiation process. We provide evidence that the regulation of BASP1 promoter occupancy involves the sumoylation of BASP1. Our results reveal a dynamic cooperation between WT1 and BASP1 in the regulation of gene expression during differentiation.
Central pattern generator (CPG) networks coordinate the generation of rhythmic activity such as locomotion and respiration. Their development is driven by various transcription factors, one of which is the Wilms tumor protein (Wt1). It is present in dI6 neurons of the mouse spinal cord, and involved in the coordination of locomotion. Here we report about the presence of Wt1 in neurons of the caudoventral medulla oblongata and their impact on respiration. By employing immunohistofluorescence staining, we were able to characterize these Wt1 positive (+) cells as dB4 neurons. The temporal occurrence of Wt1 suggests a role for this transcription factor in the differentiation of dB4 neurons during embryonic and postnatal development. Conditional knockout of Wt1 in these cells caused an altered population size of V0 neurons already in the developing hindbrain, leading to a decline in the respiration rate in the adults. Thereby, we confirmed and extended the previously proposed similarity between dB4 neurons in the hindbrain and dI6 neurons of the spinal cord, in terms of development and function. Ablation of Wt1+ dB4 neurons resulted in the death of neonates due to the inability to initiate respiration, suggesting a vital role for Wt1+ dB4 neurons in breathing. These results expand the role of Wt1 in the CNS and show that, in addition to its function in differentiation of dI6 neurons, it also contributes to the development of dB4 neurons in the hindbrain that are critically involved in the regulation of respiration.
WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity.
The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.
Few reports suggested a prognostic impact of Wilms'Tumor-1 (WT1)-mRNA overexpression in MDS, but translation into clinical routine was hampered by limited patients numbers, differing sample sources, non-standardized methods/cut-offs. To evaluate whether WT1-mRNA expression yields additional prognostic information, we measured peripheral blood (PB) WT1-mRNA expression in 94 MDS using a standardized assay offering a validated cut-off to discriminate between normal and WT1-mRNA overexpression. Overall, 54 patients (57%) showed WT1-mRNA overexpression, while 40 patients (43%) had normal WT1-mRNA expression. This enabled discrimination between MDS and both healthy controls and non-MDS cytopenias. Furthermore, WT1-mRNA expression correlated with WHO 2016 subcategories and IPSS-R as indicated by mean WT1-mRNA expression and frequency of WT1-mRNA overexpressing patients within respective subgroups. Regarding the entire group, PB WT1-mRNA expression was associated with prognosis, as those patients showing WT1-mRNA overexpression had higher risk for disease progression and AML transformation and accordingly shorter progression-free, leukemia-free and overall survival in univariate analysis. In multivariate analysis, prognostic impact of PB WT1-mRNA expression status was independent of IPSS-R and enabled more precise prediction of PFS, but not OS, within IPSS-R very low/low and intermediate risk groups. Overall, measuring PB WT1-mRNA appears valuable to support diagnostics and refine prognostication provided by the IPSS-R.
In mammals, the Wilms' tumor suppressor gene, Wt1, encodes a transcription factor critical for development of the urogenital system. In teleost fish, however, two wt1 genes have been identified. In medaka wt1a is expressed in the lateral plate mesoderm during early embryogenesis. Later in development, wt1a is additionally expressed in the somatic cells of the gonadal primordium. We show here for the first time that in teleosts wt1 gene expression is observed during gonad development. Wt1b is expressed later during embryogenesis and is not expressed in the gonadal primordium. Analysis of morpholino knockdown experiments revealed functions of wt1 genes in pronephros development. Unexpectedly, by down-regulating Wt1a protein we observed wt1b expression during embryogenesis in the wildtype wt1a expression domains including somatic cells of the gonadal primordium. Interestingly, neither wt1a nor wt1b morphants showed effects on the gonad development, whereas the double knockdown of wt1a and wt1b displayed strong influences on the number of primordial germ cell (PGC) during gonad development. Our results indicate that medaka wt1 co-orthologs show genetic redundancy in PGC maintenance or survival through responsive backup circuits. This provides first evidence for a conditional co-regulation of these genes within a transcriptional network.
Hypoxia-inducible factors (HIFs) play a key role in the adaptation to low oxygen by interacting with hypoxia response elements (HREs) in the genome. Cellular levels of the HIF-2α transcription factor subunit influence the histopathology and clinical outcome of neuroblastoma, a malignant childhood tumor of the sympathetic ganglia. Expression of the Wilms tumor gene, WT1, marks a group of high-risk neuroblastoma. Here, we identify WT1 as a downstream target of HIF-2α in Kelly neuroblastoma cells. In chromatin immunoprecipitation assays, HIF-2α bound to a HRE in intron 3 of the WT1 gene, but not to another predicted HIF binding site (HBS) in the first intron. The identified element conferred oxygen sensitivity to otherwise hypoxia-resistant WT1 and SV40 promoter constructs. Deletion of the HBS in the intronic HRE by genome editing abolished WT1 expression in hypoxic neuroblastoma cells. Physical interaction between the HRE and the WT1 promoter in normoxic and hypoxic Kelly cells was shown by chromosome conformation capture assays. These findings demonstrate that binding of HIF-2α to an oxygen-sensitive enhancer in intron 3 stimulates transcription of the WT1 gene in neuroblastoma cells by hypoxia-independent chromatin looping. This novel regulatory mechanism may have implications for the biology and prognosis of neuroblastoma.
The list of long non-coding RNAs (lncRNAs) that participate in the function of ovarian granulosa cells (GCs) is rapidly expanding, but the mechanisms through which lncRNAs regulate GC function are not yet fully understood. Here, we recognized a minimally expressed lncRNA RP4-545C24.1 (which we named DDGC) in GCs from patients with biochemical premature ovarian insufficiency (bPOI). We further explored the role of lncRNA DDGC in GC function and its contribution to the development of bPOI. Mechanistically, silencing DDGC downregulated RAD51 by competitively binding with miR-589-5p, and this resulted in significant inhibition of DNA damage repair capacity. In addition, decreased expression of DDGC promoted ubiquitin-mediated degradation of Wilms tumor 1 (WT1) protein through interactions with heat shock protein 90 (HSP90), which led to aberrant differentiation of GCs. Moreover, DDGC was able to ameliorate the etoposide-induced DNA damage and apoptosis in vivo. Taken together, these findings provide new insights into the contribution of lncRNAs in POI pathogenesis.
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