| The Wilms tumor suppressor WT1 is a zinc finger transcription factor essential for normal renal development and most highly expressed in glomerular epithelial cells, called podocytes, within developing and mature kidneys. Kidneys fail to form in wt1-null mice, and reduced expression levels are associated with defects in glomerular development and function. A similar phenotype is seen in patients with Denys-Drash syndrome (DDS), who harbor heterozygous germline mutations in the WT1 gene. Alternative pre-mRNA splicing of the WT1 transcript leads to the variable insertion of three amino acids, lysine, threonine, and serine (KTS), between zinc fingers three and four of the encoded protein. I have found that inducible expression of WT1(-KTS) in a rat embryonic kidney stem cell line leads to the induction of podocalyxin, the major structural membrane protein of glomerular podocytes, which is coexpressed with WT1 during kidney differentiation. The induction of podocalyxin supports a role for WT1 in the activation of a glomerular differentiation program in renal precursors, and its reduction may contribute to the glomerulopathy observed in DDS. In contrast to WT1(-KTS), inducible expression of WT1(+KTS) does not lead to any reproducible changes in gene expression.;The presence of a reciprocal chromosomal translocation, t(11;22)(p13;q12), resulting in the fusion of the N-terminal transactivation domain of EWS to the C-terminal three zinc fingers of WT1, is diagnostic for desmoplastic small round cell tumor (DSRCT). EWS-WT1 encodes a strong transcriptional activator whose target genes are presumably responsible for the formation of DSRCT. I used cells with inducible expression of EWS-WT1(-KTS) to screen high-density oligonucleotide microarrays, identifying a novel transcriptional target, BAIAP3, which encodes a protein implicated in regulated exocytosis: it shares homology with known regulators of this process and is colocalized with a secreted growth factor within cytoplasmic organelles. BAIAP3 is expressed within tumor cells in primary DSRCT specimens, and a human tumor cell line with ectopic expression of BAIAP3 consistently demonstrates enhanced proliferation in low serum conditions and colony formation in soft agar. BAIAP3 therefore encodes a transcriptional target of EWS-WT1 that may implicate the regulated exocytotic pathway in the secretion of growth factors contributing to cancer cell proliferation. |
