The human sex-determining gene SRY is a direct target of WT1.
The product of the Wilms' tumor gene, WT1, is essential for male sex determination and differentiation in mammals. In addition to causing Wilms' tumor, mutations in WT1 often cause two distinct but overlapping urogenital defects in men, Denys-Drash syndrome and Frasier syndrome. In this study we investigated the regulation of the sex determination gene SRY by WT1. Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA-binding sequences in the core promoter. Mutant WT1 proteins in Denys-Drash syndrome patients were unable to activate this promoter. These mutants did not act in a dominant negative manner, as expected over the wild-type WT1 in this promoter. We also found that WT1 could transactivate the endogenous SRY gene. These observations, together with the overlapping expression patterns of WT1 and SRY in human gonads, led us to propose that WT1 regulates SRY in the initial sex determination process in humans and activates a cascade of genes ultimately leading to the complete organogenesis of the testis.
Department of Biochemistry and Molecular Biology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Hossain
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Saunders
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D012734:Disorders of Sex Development / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016162:Genes, Wilms Tumor; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D009687:Nuclear Proteins; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein; D013577:Syndrome; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors; D025721:WT1 Proteins; D008156:Luciferases