The Wilms' tumor suppressor gene WT1 is negatively autoregulated

Abstract

The Wilms' tumor suppressor gene WT1 encodes a zinc-finger DNA-binding protein that functions as a transcriptional repressor. WT1 is expressed in a dramatic spatial and temporal pattern during kidney development and is thought to be critical during mesenchymal-epithelial conversion. The WT1 protein bound multiple sites in the WT1 promoter and functioned as a powerful transcriptional repressor of its gene in vivo (> 50-fold). The WT1 protein carrying an NH2-terminal 17-amino acid insertion and a 3-amino acid insertion (KTS) between zinc fingers 3 and 4, arising from the most abundant of four alternatively spliced transcripts, was the most powerful repressor. Of importance, a subset of WT1-binding sites differs from the Egr-1 consensus sequence, which has been shown to bind one splice variant of the WT1 protein (WT1(-KTS)). We characterized two of these sites and show that they bind both -KTS and +KTS forms of the WT1 zinc-finger protein and can confer repression on a heterologous promoter construct. Our data demonstrate that WT1, in addition to its known effects on insulin-like growth factor II, platelet-derived growth factor A, and Pax-2 transcription, is a powerful repressor of its own gene. These observations emphasize its critical role as a transcriptional regulatory protein during normal kidney development.