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

Expression of the Wilms' tumour suppressor gene, WT1, is tightly regulated during nephrogenesis, and loss of function of its gene product correlates with malignancy. By using luciferase reporter gene constructs containing DNA sequences from the first intron of the WT1 gene, we have identified an antisense WT1 promoter operational in the opposite direction relative to the 5' promoter. Transcription directed by the promoter is negatively regulated by upstream elements, but is activated by expression of WT1. This effect of WT1 is reciprocal to that observed on the 5' promoter, suggesting that antisense promoter activity is involved in WT1 gene regulation. By mimicking expression of the transcript regulated by the antisense promoter, we demonstrate that cellular levels of WT1 can be effectively down-regulated by antisense mRNA complementary to sequences in the first exon of WT1.