TRANSCRIPTIONAL ACTIVATION OF THE SYNDECAN-1 PROMOTER BY THE WILMS-TUMOR PROTEIN WT1

The Wilms' tumor suppressor gene (wt1) encodes a zinc finger DNA bindi ng protein (WT1) which functions as a transcriptional regulator and is essential for normal urogenital development. WT1 has previously been shown to repress the transcription of a variety of target genes whose products stimulate growth, such as growth factors, growth factor recep tors and other transcription factors. In this study, we identify synde can-1 as a target gene for WT1-mediated activation. Syndecan-1 is a ce ll surface proteoglycan whose induction is coincident with epithelial differentiation during kidney development and whose loss of expression is correlated with the loss of the epithelial phenotype and malignant transformation. The murine syndecan-1 promoter contains several poten tial binding sites for WT1. We demonstrate that both WT1 (-KTS) and WT 1 (+KTS) isoforms bind to multiple sites in this highly G+C-rich regio n, as detected by gel-shift analyses. These WT1 isoforms function as t ranscriptional activators of syndecan-1 expression in transient transf ection assays. Activation of syndecan-1 by WT1 is dependent on an inta ct zinc-finger region as well as a 179 amino acid proline-rich region in the amino terminus of the protein. Moreover, the endogenous syndeca n-1 gene is activated by WT1 in a novel inducible cell line based upon the sheep metallothionein promoter. These results highlight an emergi ng role for WT1 as an activator of genes like syndecan-1 which may pot entiate epithelial differentiation and maintenance in the developing k idney.