共查询到20条相似文献,搜索用时 15 毫秒
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The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene. 总被引:16,自引:0,他引:16
Z Y Wang S L Madden T F Deuel F J Rauscher 《The Journal of biological chemistry》1992,267(31):21999-22002
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WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. 总被引:16,自引:0,他引:16
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M W Mayo C Y Wang S S Drouin L V Madrid A F Marshall J C Reed B E Weissman A S Baldwin 《The EMBO journal》1999,18(14):3990-4003
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Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. 总被引:47,自引:0,他引:47
J Pelletier W Bruening C E Kashtan S M Mauer J C Manivel J E Striegel D C Houghton C Junien R Habib L Fouser 《Cell》1991,67(2):437-447
Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development. 相似文献
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Cyclin E is a target of WT1 transcriptional repression 总被引:5,自引:0,他引:5
Loeb DM Korz D Katsnelson M Burwell EA Friedman AD Sukumar S 《The Journal of biological chemistry》2002,277(22):19627-19632
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Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions 总被引:3,自引:0,他引:3
Scharnhorst V Dekker P van der Eb AJ Jochemsen AG 《The Journal of biological chemistry》2000,275(14):10202-10211
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Lahiri D Dutton JR Duarte A Moorwood K Graham CF Ward A 《Molecular reproduction and development》2007,74(3):300-311
The Wilms' tumour suppressor protein, WT1, is a zinc finger protein essential for the development of several organs, including the kidney and gonads. In each of these tissues WT1 is required at multiple stages of development and its persistent expression in podocytes and Sertoli cells suggests WT1 may also have a role in the maintenance of kidney and testis function throughout adult life. Naturally occurring isoforms of WT1 are generated by alternative mRNA splicing. An altered ratio of the splice isoforms WT1-KTS and WT1 + KTS appears to be sufficient to account for the developmental abnormalities (pseudohermaphroditism and nephropathy) characteristic of Frasier syndrome. We show that mice with a transgene encoding WT1-KTS do not differ from their wild-type littermates unless they are also heterozygous for a null mutation at the endogenous Wt1 locus. Animals with both genetic modifications develop proteinuria, together with multiple glomerular cysts, and male infertility. These pathologic changes may be explained as a consequence of altering the WT1 isoform ratio in tissues that express WT1 during adulthood. The results suggest WT1 misexpression could contribute to human glomerulocystic kidney disease. 相似文献
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Wilms tumor and the WT1 gene 总被引:24,自引:0,他引:24
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Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression. 总被引:4,自引:2,他引:2
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H Werner Z Shen-Orr F J Rauscher rd J F Morris C T Roberts Jr D LeRoith 《Molecular and cellular biology》1995,15(7):3516-3522
We have investigated the regulation of the insulin-like growth factor I receptor (IGF-I-R) gene promoter by the Wilms' tumor suppressor WT1 in intact cells. The levels of endogenous IGF-I-R mRNA and the activity of IGF-I-R gene promoter fragments in luciferase reporter constructs were found to be significantly higher in G401 cells (a Wilms' tumor-derived cell line lacking detectable WT1 mRNA) than in 293 cells (a human embryonic kidney cell line which expresses significant levels of WT1 mRNA). To study whether WT1 could suppress the expression of the endogenous IGF-I-R gene, WT1-negative G401 cells were stably transfected with a WT1 expression vector. Expression of WT1 mRNA in G401 cells resulted in a significant decrease in the rate of cellular proliferation, which was associated with a reduction in the levels of IGF-I-R mRNA, promoter activity, and ligand binding and with a reduction in IGF-I-stimulated cellular proliferation, thymidine incorporation, and anchorage-independent growth. These data suggest that a major aspect of the action of the WT1 tumor suppressor is the repression of IGF-I-R gene expression. 相似文献
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Mice lacking the 68-amino-acid,mammal-specific N-terminal extension of WT1 develop normally and are fertile
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Miles CG Slight J Spraggon L O'Sullivan M Patek C Hastie ND 《Molecular and cellular biology》2003,23(7):2608-2613
Mutations in the Wilms' tumor 1 gene, WT1, cause pediatric nephroblastoma and the severe genitourinary disorders of Frasier and Denys-Drash syndromes. High levels of WT1 expression are found in the developing kidney, uterus, and testis--consistent with this finding, the WT1 knockout mouse demonstrates that WT1 is essential for normal genitourinary development. The WT1 gene encodes multiple isoforms of a zinc finger-containing protein by a combination of alternative splicing and alternative translation initiation. The use of an upstream, alternative CUG translation initiation codon specific to mammals results in the production of WT1 protein isoforms with a 68-amino-acid N-terminal extension. To determine the function in vivo of mammal-specific WT1 isoforms containing this extension, gene targeting was employed to introduce a subtle mutation into the WT1 gene. Homozygous mutant mice show a specific absence of the CUG-initiated WT1 isoforms yet develop normally to adulthood and are fertile. Detailed histological analysis revealed normal development of the genitourinary system. 相似文献
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An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor 总被引:47,自引:0,他引:47
D A Haber A J Buckler T Glaser K M Call J Pelletier R L Sohn E C Douglass D E Housman 《Cell》1990,61(7):1257-1269
We have recently described the isolation of a candidate for the Wilms' tumor susceptibility gene mapping to band p13 of human chromosome 11. This gene, primarily expressed in fetal kidney, appears to encode a DNA binding protein. We now describe a sporadic, unilateral Wilms' tumor in which one allele of this gene contains a 25 bp deletion spanning an exon-intron junction and leading to aberrant mRNA splicing and loss of one of the four zinc finger consensus domains in the protein. The mutation is absent in the affected individual's germline, consistent with the somatic inactivation of a tumor suppressor gene. In addition to this intragenic deletion affecting one allele, loss of heterozygosity at loci along the entire chromosome 11 points to an earlier chromosomal nondisjunction and reduplication. We conclude that inactivation of this gene, which we call WT1, is part of a series of events leading to the development of Wilms' tumor. 相似文献
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WT1 and glomerular function 总被引:6,自引:0,他引:6
The Wilms' Tumour 1 (WT1) gene plays an important role at three different stages of kidney development. The onset of kidney formation, the progression of kidney formation and the maintenance of normal kidney function. Disruption of WT1 may lead to a whole spectrum of kidney diseases ranging from tumour development to mild forms of renal failure. However, the underlying mechanisms are largely unknown. The WT1 proteins have been implicated in various cellular processes like proliferation, differentiation and apoptosis and in agreement with these diverse functions, the number of target genes is still mounting. The development of mouse models in recent years has contributed considerably to a better understanding of the biological activities of WT1, and in this article we will discuss the role of WT1 during kidney formation and kidney function. 相似文献
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