REPRESSION OF THE TRANSFORMING GROWTH-FACTOR-BETA-1 GENE BY THE WILMS-TUMOR SUPPRESSOR WT1 GENE-PRODUCT

The Wilms' tumor suppressor gene (WT1) encodes a zinc finger DNA binding protein which functions as a transcriptional repressor. In this study we investigated whether the human transforming growth factor-beta 1 (TGF-beta 1) gene might be a target for transcriptional repression mediated by WT1. Using constructs of the TGF-beta 1 promoter linked to the chloramphenicol acetyl transferase gene, we have demonstrated that the WT1 protein represses expression of the TGF-beta 1 gene through a CGCCCCCGC response element spanning nucleotides -111 to -119 of the TGF-beta 1 promoter. We have also shown in a cotransfection assay that Egr-1, an immediate early growth response gene, activates transcription of the TGF-beta 1 gene through the same response element and that WT1 represses both the basal and Egr-1-induced TGF-beta 1 promoter activity in monkey kidney CV-1 cells. Moreover, WT1 and Egr-1 proteins interact directly with the WT1/Egr-1 response element of the TGF-beta 1 promoter in gel mobility shift assays. These findings provide further definition of transcriptional control of the TGF-beta 1 gene by showing that the WT1 gene product suppresses TGF-beta 1 transcription and that the WT1/Egr-1 consensus element of the human TGF-beta 1 promoter plays a critical role in this repression.