PAX8-mediated activation of the wt1 tumor suppressor gene

The developing renal system has long been exploited to study the regulation of gene expression during mesenchymal-epithelial transitions. Several transcription factors, including WT1 and PAX8, are expressed early in nephrogenesis and play a key role in this process. The expression of PAX8 occurs in the induced mesenchyme of the developing kidney prior to the upregulation of WT1 levels in the same cells. In this report, we assessed whether the Pax-8 gene product resides upstream of wt1 in a common regulatory pathway. Transfection studies, as well as gel-shift assays, indicate that PAX8 transactivates wt1 through elements within a 38 bp conserved motif, present in human and murine promoters. Two PAX8 isoforms, generated by alternative splicing at the C-terminus and previously thought to lack transactivation potential, were found to be capable of activating wt1 expression. We also demonstrate that the endogenous wt1 promoter can be upregulated by exogenously supplied PAX8, suggesting that a function of PAX8 during mesenchymal--epithelial cell transition in renal development is to induce wt1 gene expression.