REPRESSION OF THE RETINOIC ACID RECEPTOR-ALPHA GENE BY THE WILMS-TUMOR SUPPRESSOR GENE-PRODUCT, WT1

The Wilms' tumor (WT) suppressor gene, WT1, encodes a zinc finger DNA binding protein (wt1) which functions as a transcriptional regulator. Germline WT1 mutations predispose to WTs and in many cases are associa ted with urogenital anomalies. Identification of wt1 downstream target s is essential to understanding regulatory processes involved in devel opment of this system. In this study, we demonstrate that wt1 can repr ess transcription of the retinoic acid receptor-alpha 1 (RAR-alpha 1) promoter. Transient transfection, deletion mutagenesis, and mobility s hift assays suggest that wt1 mediates repression of the human RAR-alph a 1 promoter through a GC-rich DNA binding motif (5'-GCGGGGGCG-3'), at positions -111 to -120 bp (relative to the transcription initiation s ite). In contrast, the murine RAR-alpha 1 promoter contains a cryptic binding motif and is not responsive to wt1. These results indicate tha t some wt1-regulatory pathways are not conserved across species, sugge sting a molecular basis for differences in phenotypes between humans a nd mice harboring WT1 lesions.