title: Antagonism of WT1 activity by protein self-association.
abstract: Germline loss-of-function mutations at the Wilms tumor (WT) suppressor locus WT1 are associated with a predisposition to WTs and mild genital system anomalies. In contrast, germ-line missense mutations within the WT1 gene encoding the DNA-binding domain often yield a more severe phenotype consisting of WT, sexual ambiguity, and renal nephropathy. In this report, we demonstrate that the products of mutant alleles that impair DNA recognition can antagonize WT1-mediated transcriptional repression. We demonstrate that WT1 can self-associate in vitro and in vivo and that the responsible domain maps to the amino-terminal region of the protein. Oligomers of full-length protein form less efficiently or produce less stable complexes than oligomers between truncated polypeptides and full-length protein. Our data suggest a molecular mechanism to explain how WT1 mutations may act in deregulating cellular proliferation and differentiation.
mesh_terms: D000483:Alleles; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor; D006801:Humans; D046911:Macromolecular Substances; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011994:Recombinant Proteins; D012097:Repressor Proteins / Q000737:chemistry*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics; D015533:Transcriptional Activation; D025721:WT1 Proteins
chemical_list: D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025721:WT1 Proteins