THE PAIRED-BOX TRANSCRIPTION FACTOR, PAX2, POSITIVELY MODULATES EXPRESSION OF THE WILMS-TUMOR SUPPRESSOR GENE (WT1)

The Wilms' tumor suppressor gene, wt1, encodes a zinc finger protein w hich functions as a transcriptional regulator. Expression of the wt1 g ene is developmentally regulated and restricted to a small set of tiss ues which include the fetal urogenital system, mesothelium, and spleen . In the developing kidney, induction of neprohogenesis by the ureter is accompanied by an increase in expression levels of the Pax-2 gene, a developmentally and spatially regulated paired-box member. This is f ollowed by an increase in wt1 expression as mesenchymal cells condense and differentiate. In this report, we demonstrate that PAX2 isoforms are capable of transactivating the wt1 promoter. Deletion mutagenesis of the wt1 promoter identified an element responsible for mediating PA X2 responsiveness, located between nucleotides -33 and -71 relative to the first wt1 transcription start site. Consistent with its identity as a PAX responsive element, multimerization of this mofit upstream of a heterologous minimal promoter enhanced reporter activity when co-tr ansfected with a Pax-2 expression vector. Finally, we demonstrate that PAX2 can stimulate expression of the endogenous wt1 gene. These resul ts suggest that a role for mesenchyme-to-epithelium transition in ment is to induce wt1 expression.