title: WT1, the Wilms' tumor suppressor gene product, represses transcription through an interactive nuclear protein.
abstract: The Wilms' tumor suppressor gene, wt1, encodes a transcription factor of the zinc finger family. Mutations in WT1 have been detected in subsets of Wilms' tumor and in patients with the Denys-Drash Syndrome. In order to determine how WT1 regulates transcription and perhaps the consequences that mutations in WT1 may have, we established that residues 85-124 and 181-250 of WT1 constitute domains that function independently with a DNA binding domain to repress or activate transcription, respectively, and function equally effectively with heterologous promoters, suggesting the activator and repressor domains interact with nuclear components of general importance. To seek evidence for such components, increasing concentrations of WT1 repressor domain without a zinc finger DNA binding domain were co-transfected with fixed concentrations of wild-type (wt) WT1 and PDGF A-chain promoter/reporter gene constructs. As levels of the repressor domain were increased, a progressive loss of wt WT1 repressor activity and a progressive increase in its activation were observed, suggesting that the repressor domain of WT1 competes with wt WT1 for an interactive protein that is an essential component of the repressor activity of wt WT1. Because the most common mutation associated with Denys-Drash Syndrome disrupts the zinc finger domains of WT1, the results also suggest that the mutant WT1 may have aberrant DNA binding activity and perhaps function as a dominant negative effector of wt WT1.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.forename: Q Q
authors.initials: QQ
authors.lastname: Qiu
authors.forename: M
authors.initials: M
authors.lastname: Gurrieri
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: T F
authors.initials: TF
authors.lastname: Deuel
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D025721:WT1 Proteins
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase