Antagonism of WT1 activity by protein self-association - PubMed (original) (raw)

Antagonism of WT1 activity by protein self-association

P Moffett et al. Proc Natl Acad Sci U S A. 1995.

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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References

1. Hum Genet. 1981;57(3):231-46 - PubMed
1. J Biol Chem. 1995 May 5;270(18):10878-84 - PubMed
1. Nature. 1990 Feb 22;343(6260):774-8 - PubMed
1. Cell. 1991 Oct 18;67(2):437-47 - PubMed
1. Science. 1992 May 15;256(5059):1014-8 - PubMed

Antagonism of WT1 activity by protein self-association - PubMed (original) (raw)