Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The Wilms tumour (WT1) gene was first localized through its deletion in individuals with the WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation). Such individuals have a 30-50% lifetime risk of developing Wilms tumour and carry constitutional interstitial deletions of chromosome 11p13, including the WT1 gene. Second primary tumours occurring in such individuals might also be related to their genetic predisposition to cancer, as shown for hereditary retinoblastoma. We have found a mutation in the zinc finger region of the remaining WT1 allele in a case of acute myeloid leukaemia developing in a Wilms tumour survivor with the WAGR syndrome. This mutation would be predicted to disrupt DNA binding by this developmentally regulated transcription factor. This finding implicates the WT1 gene in the regulation of myelopoiesis and suggests that WT1 mutations may be found in some sporadic leukaemias.
Hum Mol Genet 1994 Sep
PMID:The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. 783 22

The Wilms' tumor suppressor gene, WT1, encodes a zinc finger polypeptide which plays a key role regulating cell growth and differentiation in the urogenital system. Using the whole-genome PCR approach, we searched murine genomic DNA for high-affinity WT1 binding sites and identified a 10-bp motif 5'GCGTGGGAGT3' which we term WTE). The WTE motif is similar to the consensus binding sequence 5'GCG(G/T)GGGCG3' recognized by EGR-1 and is also suggested to function as a binding site for WT1, setting up a competitive regulatory loop. To evaluate the underlying biochemical basis for such competition, we compared the binding affinities of WT1 and EGR1 for both sequences. WT1 shows a 20- to 30-fold-higher affinity for the WTE sequence compared with that of the EGR-1 binding motif. Mutational analysis of the WTE motif revealed a significant contribution to binding affinity by the adenine nucleotide at the eighth position (5'GCGTGGGAGT3') as well as by the 3'-most thymine (5'GCGTGGGAGT3'), whereas mutations in either flanking nucleotides or other nucleotides in the core sequence did not significantly affect the specific binding affinity. Mutations within WT1 zinc fingers II to IV abolished the sequence-specific binding of WT1 to WTE, whereas alterations within the first WT1 zinc finger reduced the binding affinity approximately 10-fold but did not abolish sequence recognition. We have thus identified a WT1 target, which, although similar in sequence to the EGR-1 motif, shows a 20- to 30-fold-higher affinity for WT1. These results suggest that physiological action of WT1 is mediated by binding sites of significantly higher affinity than the 9-bp EGR-1 binding motif. The role of the thymine base in contributing to binding affinity is discussed in the context of recent structural analysis.
Mol Cell Biol 1995 Mar
PMID:Sequence and structural requirements for high-affinity DNA binding by the WT1 gene product. 786 42

The H19 gene is a parenterally imprinted maternally expressed gene which has a pivotal role in embryogenesis and fetal development. It is tightly linked to the IGF-II gene on chromosome 11p15.5 which is reciprocally imprinted. We studied the expression of the human H19 by in situ hybridization in an embryo 35 days post coitus (dpc) and in a fetus from the second trimester of pregnancy. The expression pattern of H19 in the human fetal tissues was similar to its expression in the mouse, and paralleled, with some exceptions, the expression of IGF-II in human fetuses. Abundant expression was found in organs comprising the fetoplacental unit: the placenta, the fetal adrenal, and liver. The expression in the fetal adrenal cortex was most prominent in the definitive cortex and somewhat weaker in the fetal zone. Considerable expression of H19 was found in the fetal liver as early as 35 dpc and in the second trimester. Hematopoietic cells in fetal liver did not express the gene. Moderate expression of H19 was detected in the epithelium of the small intestines, in endometrial stroma and Fallopian tube. In the kidney conspicuous labeling of the metanephric blastema was noted, which was markedly reduced with differentiation to tubules. This pattern of expression is identical to that of IGF-II in the fetal kidney and is relevant to the evolution of Wilms' tumor. No expression of H19 was found in the neural tube of the first trimester embryo or in the developing fetal brain in the second trimester, nor were transcripts detected in the choroid plexus.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Reprod Dev 1994 Jul
PMID:Expression of the imprinted gene H19 in the human fetus. 791 73

Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. IGF-II expression is activated in several types of human neoplasms and an alteration of IGF-II imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of IGF-II gene is conserved in normal adult muscle tissue whereas two or more copies of active IGF-II alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since IGF-II has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active IGF-II gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal IGF-II allele out of 7 leiomyosarcomas tested.
Hum Mol Genet 1994 Jul
PMID:Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. 798 80

The Wilms' tumor suppressor gene (WT1) encodes a zinc finger DNA binding protein which functions as a transcriptional repressor. In this study we investigated whether the human transforming growth factor-beta 1 (TGF-beta 1) gene might be a target for transcriptional repression mediated by WT1. Using constructs of the TGF-beta 1 promoter linked to the chloramphenicol acetyl transferase gene, we have demonstrated that the WT1 protein represses expression of the TGF-beta 1 gene through a CGCCCCCGC response element spanning nucleotides -111 to -119 of the TGF-beta 1 promoter. We have also shown in a cotransfection assay that Egr-1, an immediate early growth response gene, activates transcription of the TGF-beta 1 gene through the same response element and that WT1 represses both the basal and Egr-1-induced TGF-beta 1 promoter activity in monkey kidney CV-1 cells. Moreover, WT1 and Egr-1 proteins interact directly with the WT1/Egr-1 response element of the TGF-beta 1 promoter in gel mobility shift assays. These findings provide further definition of transcriptional control of the TGF-beta 1 gene by showing that the WT1 gene product suppresses TGF-beta 1 transcription and that the WT1/Egr-1 consensus element of the human TGF-beta 1 promoter plays a critical role in this repression.
Mol Endocrinol 1994 May
PMID:Repression of the transforming growth factor-beta 1 gene by the Wilms' tumor suppressor WT1 gene product. 805 69

We have examined insulin-like growth factor 1 receptor (IGF1R) gene expression for evidence of imprinting in 15 informative patients with embryonal tumours. Biallelic expression was observed in all but one sample of normal juvenile kidney and liver, and in 9/10 associated Wilms' tumours, 3/3 hepatoblastomas and 2/2 adrenal tumours. A single patient with Beckwith-Wiedemann Syndrome (BWS) demonstrated monoallelic expression of the maternally derived IGF1R allele in normal kidney, associated Wilms' tumour and in peripheral blood lymphocytes. The observed biallelic expression of the IGF1R gene in all but one patient strongly suggests that the human gene is not normally imprinted.
Hum Mol Genet 1993 Dec
PMID:The insulin-like growth factor 1 receptor gene is normally biallelically expressed in human juvenile tissue and tumours. 811 78

MIG1 is a zinc finger protein that mediates glucose repression in the yeast Saccharomyces cerevisiae. MIG1 is related to the mammalian Krox/Egr, Wilms' tumor, and Sp1 finger proteins. It has two fingers and binds to a GCGGGG motif that resembles the GC boxes recognized by these mammalian proteins. We have performed a complete saturation mutagenesis of a natural MIG1 site in order to elucidate its binding specificity. We found that only three mutations within the GC box retain the ability to bind MIG1: G1 to C, C2 to T, and G5 to A. This result is consistent with current models for zinc finger-DNA binding, which assume that the sequence specificity is determined by base triplet recognition within the GC box. Surprisingly, we found that an AT-rich region 5' to the GC box also is important for MIG1 binding. This AT box is present in all natural MIG1 sites, and it is protected by MIG1 in DNase I footprints. However, the AT box differs from the GC box in that no single base within it is essential for binding. Instead, the AT-rich nature of this sequence seems to be crucial. The fact that AT-rich sequences are known to increase DNA flexibility prompted us to test whether MIG1 bends DNA. We found that binding of MIG1 is associated with bending within the AT box. We conclude that DNA binding by a simple zinc finger protein such as MIG1 can involve both recognition of the GC box and flanking sequence preferences that may reflect local DNA bendability.
Mol Cell Biol 1994 Mar
PMID:Importance of a flanking AT-rich region in target site recognition by the GC box-binding zinc finger protein MIG1. 811 29

The Wilms' tumor suppressor, WT1, is a zinc finger transcriptional regulator which exists as multiple forms owing to alternative mRNA splicing. The most abundant splicing variants contain a nine-nucleotide insertion encoding lysine, threonine, and serine (KTS) in the H-C link region between the third and fourth WT1 zinc fingers which disrupts binding to a previously defined WT1-EGR1 binding site. We have identified WT1[+KTS] binding sites in the insulin-like growth factor II gene and show that WT1[+KTS] represses transcription from the insulin-like growth factor II P3 promoter. The highest affinity WT1[+KTS] DNA binding sites included nucleotide contacts involving all four WT1 zinc fingers. We also found that different subsets of three WT1 zinc fingers could bind to distinct DNA recognition elements. A tumor-associated, WT1 finger 3 deletion mutant was shown to bind to juxtaposed nucleotide triplets for the remaining zinc fingers 1, 2, and 4. The characterization of novel WT1 DNA recognition elements adds a new level of complexity to the potential gene regulatory activity of WT1. The results also present the possibility that altered DNA recognition by the dominant WT1 zinc finger 3 deletion mutant may contribute to tumorigenesis.
Mol Cell Biol 1994 Jun
PMID:DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1. 819 23

The MSN2 gene was selected as a multicopy suppressor in a temperature-sensitive SNF1 protein kinase mutant of Saccharomyces cerevisiae. MSN2 encodes a Cys2His2 zinc finger protein related to the yeast MIG1 repressor and to mammalian early growth response and Wilms' tumor zinc finger proteins. Deletion of MSN2 caused no phenotype. A second similar zinc finger gene, MSN4, was isolated, and deletion of both genes caused phenotypic defects related to carbon utilization. Overexpression of the zinc finger regions was deleterious to growth. LexA-MSN2 and LexA-MSN4 fusion proteins functioned as strong transcriptional activators when bound to DNA. Functional roles of this zinc finger protein family are discussed.
Mol Cell Biol 1993 Jul
PMID:Two homologous zinc finger genes identified by multicopy suppression in a SNF1 protein kinase mutant of Saccharomyces cerevisiae. 832 Nov 94

The triad of nephropathy, partial gonadal dysgenesis and Wilms' tumour (WT) is known as Denys-Drash syndrome (DDS). The WT predisposition gene WT1, which plays a vital role in both genital and renal development, is known to be mutated in DDS patients. The WT1 mutations in these patients are constitutional point mutations clustered in the zinc finger (ZF) encoding exons, particularly the exons encoding ZF2 and ZF3. The predicted functional alteration in WT1 is thought to underlie DDS aetiology either by abolishing binding of the WT1 ZF domain to its normal target DNA binding site(s), perhaps blocking the binding of the wild type WT1 present (dominant negative mutation), and/or by conferring the ability to recognise novel but inappropriate DNA binding sites (dominant mutation). We report here on the analysis of WT1 in a further five cases of DDS. In each case a constitutional point mutation was detected in either ZF2 or ZF3. Three of these mutations are novel, with two affecting the conserved histidine and cysteine residues crucial for ZF tertiary structure. The protein product of the third is predicted to lack ZF2, 3 and 4 as a result of a chain termination mutation, and is presumably incapable of binding DNA. However since the DDS phenotype is only elicited by mutations which lead to loss or alteration of ZF function (presumably DNA binding) while the N-terminal upstream portion of the gene remains intact, we suggest that a dominant negative mechanism is at work here.
Hum Mol Genet 1993 Mar
PMID:Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. 838 65


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