The role of NF-kappaB in the regulation of the expression of wilms tumor suppressor gene WT1.

The Wilms tumor suppressor gene, WT1, plays an important role in genitourinary development and the etiology of Wilms tumor. WT1 has a spatially and temporally defined expression in the developing genitourinary system and in specific cells of the hematopoietic system, but the regulatory pathways that control WT1 expression are not well understood. Recently, members of the NF-kappaB family of transcription factors have been proposed as potent activators of the murine WT1 promoter through binding to a NF-kappaB site. Because the human WT1 promoter contains a conserved NF-kappaB site, we investigated whether NF-kappaB also regulates the expression of the human WT1 gene. We activated NF-kappaB through cytokine stimulation or inhibited NF-kappaB through expression of a NF-kappaB "super repressor" in WT1 expressing Wilms tumor, renal carcinoma, and erythroleukemia cultures and examined the level of endogenous WT1 gene expression. Although a transfected NF-kappaB reporter construct was responsive to these manipulations, we found that altering NF-kappaB activity had no effect on endogenous WT1 expression in the cell types used in our study. We conclude that despite the presence of conserved NF-kappaB elements in the murine and human WT1 promoters, NF-kappaB is not required to regulate the expression of the WT1 gene in its natural context.