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. 1995 Nov 21;92(24):11105–11109. doi: 10.1073/pnas.92.24.11105

Antagonism of WT1 activity by protein self-association.

P Moffett 1, W Bruening 1, H Nakagama 1, N Bardeesy 1, D Housman 1, D E Housman 1, J Pelletier 1
PMCID: PMC40580  PMID: 7479946

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.

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Selected References

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