IDENTIFICATION OF AN ANTISENSE WT1 PROMOTER IN INTRON-1 - IMPLICATIONS FOR WT1 GENE-REGULATION

Expression of the Wilms' tumour suppressor gene, WT1, is tightly regul ated during nephrogenesis, and loss of function of its gene product co rrelates with malignancy. By using luciferase reporter gene constructs containing DNA sequences from the first intron of the WT1 gene, we ha ve identified an antisense WT1 promoter operational in the opposite di rection relative to the 5' promoter. Transcription directed by the pro moter is negatively regulated by upstream elements, but is activated b y expression of WT1. This effect of WT1 is reciprocal to that observed on the 5' promoter, suggesting that antisense promoter activity is in volved in WT1 gene regulation. By mimicking expression of the transcri pt regulated by the antisense promoter, we demonstrate that cellular l evels of WT1 can be effectively down-regulated by antisense mRNA compl ementary to sequences in the first exon of WT1.