E-cadherin Is a WT1 Target Gene

Abstract

The WT1 tumor suppressor gene encodes a transcription factor that can activate and repress gene expression. Transcriptional targets relevant for the growth suppression functions of WT1 are poorly understood. We found that mesenchymal NIH 3T3 fibroblasts stably expressing WT1 exhibit growth suppression and features of epithelial differentiation including up-regulation of E-cadherin mRNA. Acute expression of WT1 in NIH 3T3 fibroblasts after retroviral infection induced murine Ecadherin expression. In transient transfection experiments, the human and murine E-cadherin promoters were activated by co-expression of WT1. E-cadherin promoter activity was increased in cells overexpressing WT1 and was blocked by a dominant negative form of WT1. WT1 activated the murine E-cadherin promoter through a conserved GC-rich sequence similar to an EGR-1 binding site as well as through a CAAT box sequence. WT1 produced in vitro or derived from nuclear extracts bound to the WT1-response element within the murine E-cadherin promoter, but not the CAAT box. E-cadherin, a gene important in epithelial differentiation and neoplastic transformation, represents a downstream target gene that links the roles of the WT1 in differentiation and growth control.The WT1 tumor suppressor gene is associated with Wilms' tumor, which can be considered a disease of disordered development, since the tumors exhibit the three elements of primordial kidney development including blastemal, stromal, and epithelial elements (1). The WT1 gene is predominantly expressed in the developing kidney, but WT1 expression is also detected in the fetal gonad, spleen, mesothelium, breast, and other tissues (reviewed in Ref. 2). During early nephrogenesis, WT1 expression is first detected in the metanephric mesenchyme. At the onset of epithelial differentiation, WT1 expression increases as the mesenchyme surrounding the ureteric bud condenses to form primary vesicles. These cells further differentiate into comma-and S-shaped bodies, and subsequently mature into glomeruli and proximal tubules. This phenomenon and the finding that mice null for WT1 fail to develop kidneys (3) suggest an essential role for WT1 in controlling the mesenchymal-epithelial transition of renal development. WT1 differs from other tumor suppressor genes such as Rb and p53 in that Rb and p53 are widely expressed in a variety of developing and adult tissues, while WT1 expression is restricted. The restricted pattern of WT1 expression suggests that its growthsuppressive properties may be linked to its role in organogenesis.WT1 gene encodes a Cys-His zinc finger transcription factor, which functions as both a transcriptional repressor and activator (2, 4 -6). The DNA binding activity of WT1 was demonstrated on several different sequences including 5Ј-GCGGGG-GCG-3Ј, which is also recognized by EGR-1, EGR-2, and EGR-3 (4, 7-10). Alternative splicing of the WT1 gene yields four major isoforms of the WT1 protein. Isoforms C and D include a 3-amino acid (KTS) segment between zinc fingers three and four of the...

Disregulation of E-cadherin in transgenic mouse models of liver cancer

“…On the other hand, WT1 directly transactivates E-cadherin, suggesting that loss of WT1 may also repress the Ecadherin gene. 37 In order to assess whether similar relationships exist in mouse hepatocarcinogenesis, we have determined the expression levels of Snail, Slug, HIF-1a and WT1 by Western blot analysis in the same collection of mouse HCCs. The results of our analysis are shown in Figure 2.…”

Expression and mutation analysis of the Wilms' tumor 1 gene in human neural tumors

“…These include the EGFR, IGF1R, BCL2, amphiregulin, E-cadherin and ornithine decarboxylase. [1][2][3][4][5][6] WT1 can regulate transcription through both activator and suppressor functions and this is affected by the cellular environment in which it is expressed.…”

“…The precise nature of the role of WT1 in this process is however not known, although there is evidence that transactivation of the WT1 target genes, amphiregulin and E-cadherin, may be involved. 5,6 Oncogenic WT1 lesions have been identified in tumors arising in tissues of mesodermal origin including the kidney (Wilms' tumor) 8 gut-lining (Desmoplastic small round cell tumor) 9 and lungs (mesothelioma). 10 In addition, germline heterozygous WT1 zinc-finger mutations occur in Denys Drash syndrome in which patients are predisposed to the development of both Wilms' tumor and gonadoblastoma.…”

Functional Role of WT1 in Prostate Cancer

“…While initial experiments associated growth suppression and characteristics of epithelial differentiation, including upregulation of E-cadherin, with stable expression of WT1 in NIH 3T3 cells (62), more recent studies in cardiac epithelial cells showed that WT1 transcriptionally repressed E-cadherin expression both directly and indirectly by the upregulation of Snail (28). Furthermore, it has been demonstrated that WT1 expression promotes metastasis and invasion in nonsmall-cell lung carcinoma patients through the suppression of E-cadherin (90).…”

“…Initial studies in NIH-3T3 cells, in which it was demonstrated that E-cadherin is a WT1 target gene (62), and studies in cardiac epithelial cells have established the role of WT1 in E-cadherin regulation (28). E-cadherin is a transmembrane protein that mediates epithelial cell-cell interactions in the adherent junctions of the plasma membrane (63) through homophilic proteinprotein interactions (64).…”