Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the occurrence of bladder cancer is common, the molecular events underlying the pathogenesis of this cancer remain ill-defined. A loss of heterozygosity (LOH) at specific chromosomal loci may predispose individuals to the development of bladder cancer but this has not been examined in detail. Furthermore, the role that deletion or inactivation of putative tumour suppressor genes might play in the genesis of bladder cancer has not been established. In this study, allelic deletion analysis on the short arm of chromosome 17 of patients with primary bladder tumours failed to show deletion at 17p13 (0/7), a region known to contain the p53 tumour suppressor gene. Chromosome 11p15 showed allelic deletion at the IGF2 locus (2/7: 29%) and the PTH locus (1/11: 9%). However, no deletion was observed at the CALCA locus (0/6). LOH at 11p13, a region containing the Wilm's tumour suppressor gene (WT1), was also studied. Analysis of LOH at 11p13 showed deletion at the CAT locus (13/18: 72%), the delta J/D11S414 locus (5/15: 33%), the WT1 locus (7/14: 50%) and the FSHB locus (6/16: 38%). The significance of these findings is discussed.
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PMID:Loss of heterozygosity on chromosome 11p13 in primary bladder carcinoma. 810 Feb 10

Denys-Drash syndrome (DDS) is characterized by early onset nephropathy, pseudohermaphroditism in males and a high risk for developing Wilm's tumour (WT). The exact cause of DDS is unknown but germline mutations in the Wilm's tumour suppressor gene (WT1) have recently been described in the majority of DDS patients studied. These mutations occur de novo and are clustered around the zinc finger (ZF) coding exons of the WT1 gene. Analysis of exons 2-10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing. In four out of the five patients, heterozygous germline mutations were found: a novel point mutation in exon 8 (ZF2) at codon 377 altering the wild-type histidine to arginine, and three previously described point mutations in exon 9 (ZF3) in the codons corresponding to amino acids 394Arg and 396Asp. In one patient, no mutations could be demonstrated. In three patients where parental DNA was available, the mutations were shown to have occurred de novo. Furthermore, since tumour DNA in two of these cases had lost the wild-type allele, polymorphic markers from the short arm of chromosome 11 were used to determine the parental origin of the mutant chromosome. In both cases, the mutant chromosome was shown to be of paternal origin. Since the majority of published WT1 mutations in DDS patients alter a RsrII restriction site in exon 9, we were able to perform PCR-based diagnosis in a female patient with early renal insufficiency and normal external genitalia.
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PMID:WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin. 811 32

The Wilms' tumour suppressor gene 1 (WT1) (1,2) encodes four C2H2 zinc finger-containing proteins (3) critical for normal mammalian urogenital development (4). Mutations in this gene are observed in the childhood kidney cancer, Wilms' tumour (WT) (5). WT1 can bind specific DNA targets within the promoters of many genes (6-9) and both transcriptional repression and activation domains have been identified (10). On this basis, it has been assumed that regulation of transcription is the basis of WT1 tumour suppressor activity. However, subnuclear localization studies have revealed an association between WT1 proteins and 'speckled bodies' within the nucleus. Degradation of nuclear RNA in cells expressing WT1 abolishes this speckled localization and WT1 co-immunoprecipitates with a number of spliceosomal proteins, suggesting that it may also bind to RNA (11). Using structural rather than sequence comparison, we have now identified an evolutionarily conserved N-terminal RNA recognition motif (RRM) in all known WT1 isoforms similar to that in the constitutive splicing factor U1A. Given the association between WT1 mutations and Wilms' tumours, this study, together with other recent findings, may suggest a novel tumour suppression mechanism.
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PMID:An RNA recognition motif in Wilms' tumour protein (WT1) revealed by structural modelling. 858 29

The Wilms' tumour-suppressor gene (WT1), encodes a zinc-finger transcription factor that is critical for the development of several organs, including the kidneys, gonads and spleen. Despite its identification as a tumour suppressor that plays a crucial role in the formation of a paediatric malignancy of the kidneys (Wilms' tumour), it has also emerged as an oncogenic factor influencing proliferation and apoptosis in a large variety of adult cancers. This review focuses on new insights into WT1's role in early development and its potential oncogenic role in adult cancer.
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PMID:The role of the Wilms' tumour-suppressor protein WT1 in apoptosis. 1863 Nov 30

Wilms' tumour is a paediatric malignancy of the kidneys and is one of the most common solid childhood cancers. The Wilms' tumour 1 protein (WT1) is a transcription factor that can either activate or repress genes involved in growth, apoptosis and differentiation. It is frequently mutated or aberrantly expressed in Wilms' tumour, where the wild type protein would normally act as a tumour suppressor. Several studies, however, have found that wild type WT1 acts as an oncogene in adult tumours, primarily through the inhibition of apoptosis. The expression of WT1 correlates with the aggressiveness of several adult cancers, and its continued expression following treatment is indicative of a poor outcome.We recently found that the treatment of tumour cell lines with cytotoxic drugs leads to the cleavage of WT1 by the serine protease HtrA2. HtrA2 binds to a specific region of WT1, the suppression domain, and then cleaves WT1 at multiple sites. The HtrA2-mediated proteolysis of WT1 leads to its removal from gene promoter regions and changes in gene expression. Cleavage of WT1 by HtrA2 enhances apoptosis. This event is advantageous to the treatment of adult tumours where WT1 acts as an oncogene. However, when WT1 is acting as a tumour suppressor in paediatric malignancies, proteolysis by HtrA2 would be antagonistic to therapy.
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PMID:HtrA2, taming the oncogenic activities of WT1. 2054 71

Although tumour suppressor gene hypermethylation is a universal feature of cancer cells, little is known about the necessary molecular triggers. Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. Specifically, we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. Consistent with this regulatory role, immunohistochemical analysis shows co-expression of WT1 and DNMT3A proteins in nuclei of blastemal cells in human fetal kidney and Wilms' tumours. Using genome-wide promoter methylation arrays, we show that human embryonal kidney cells over-expressing WT1 acquire DNA methylation changes at specific gene promoters where DNMT3A recruitment is increased, with hypermethylation being associated with silencing of gene expression. Elevated DNMT3A is also demonstrated at hypermethylated genes in Wilms' tumour cells, including a region of long-range epigenetic silencing. Finally, we show that depletion of WT1 in Wilms' tumour cells can lead to reactivation of gene expression from methylated promoters, such as TGFB2, a key modulator of epithelial-mesenchymal transitions. Collectively, our work defines a new regulatory modality for WT1 involving elicitation of epigenetic alterations which is most likely crucial to its functions in development and disease.
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PMID:Control of epigenetic states by WT1 via regulation of de novo DNA methyltransferase 3A. 2304 85

The Wilms' tumour 1 (WT1) gene originally identified as a tumour suppressor associated with WTs encodes a zinc finger-containing transcription factor that is expressed in multiple tissues and is an important regulator of cellular and organ growth, proliferation, development, migration and survival. However, there is a deficiency of data regarding the expression and function of WT1 during oocyte maturation and preimplantation embryonic development. Herein, we sought to define the expression characteristics and functions of WT1 during oocyte maturation and preimplantation embryonic development in pigs. We show that WT1 is expressed in porcine oocytes and at all preimplantation stages in embryos generated by ICSI. We then evaluated the effects of down-regulating WT1 expression at germinal vesicle and early ICSI stages using a recombinant plasmid (pGLV3-WT1-shRNA). Down-regulation of WT1 did not affect oocyte maturation but significantly decreased preimplantation embryonic development and increased apoptosis in blastocysts. These results indicate that WT1 plays important roles in the development of porcine preimplantation embryos.
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PMID:Effects of WT1 down-regulation on oocyte maturation and preimplantation embryo development in pigs. 2503 Aug 93