ANTAGONISM OF WT1 ACTIVITY BY PROTEIN SELF-ASSOCIATION

Germline loss-of-function mutations at the Wilms tumor (WT) suppressor locus WT1 are associated with a predisposition to WTs and mild genita l system anomalies. In contrast, germ-line missense mutations within t he WT1 gene encoding the DNA-binding domain often yield a more severe phenotype consisting of WT, sexual ambiguity, and renal nephropathy. I n this report, we demonstrate that the products of mutant alleles that impair DNA recognition can antagonize WT1-mediated transcriptional re pression. We demonstrate that WT1 can self-associate in vitro and in v ivo 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 pol ypeptides and full-length protein. Our data suggest a molecular mechan ism to explain how WT1 mutations may act in deregulating cellular prol iferation and differentiation.