The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin

Abstract

WT1 encodes a zinc finger transcription factor implicated in kidney differentiation and tumorigenesis. In reporter assays, WT1 represses transcription from GC- and TC-rich promoters, but its physiological targets remain uncertain. We used hybridization to high-density oligonucleotide arrays to search for native genes whose expression is altered following inducible expression of WT1. The major target of WT1 was amphiregulin, a member of the epidermal growth factor family. The WT1(-KTS) isoform binds directly to the amphiregulin promoter, resulting in potent transcriptional activation. The in vivo expression profile of amphiregulin during fetal kidney development mirrors the highly specific pattern of WT1 itself, and recombinant Amphiregulin stimulates epithelial branching in organ cultures of embryonic mouse kidney. These observations suggest a model for WT1 as a transcriptional regulator during kidney differentiation.

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

“…In fetal kidney differentiation, the zinc-finger transcription factor Wilms tumor suppressor (WT1) has been shown to regulate amphiregulin gene expression (Lee et al, 1999), but we did not find any WT1 expression in MCF-7 cells (data not shown). Recently, BRCA1 has been described as transcriptional repressor of amphiregulin and loss of BRCA1 resulted in elevated amphiregulin protein levels (Lamber et al, 2010).…”

“…Cyclic AMP response element (CRE)-binding protein-dependent regulation of amphiregulin gene expression has been reported in the intestinal epithelial cells and a functional CRE has been identified in the human amphiregulin promoter (Plowman et al, 1990;Lee et al, 1999;O'Reilly et al, 2006). To delineate the function of CRE-binding protein in PHD2-dependent pAREG regulation, we cotransfected shPHD2 MCF-7 cells with wild-type or mutant CRE pAREG reporter plasmids together with active or mutant PHD2.…”

“…The amphiregulin promoter plasmid pAREG (À641/ þ 120) was kindly provided by SB Lee (Bethesda, USA) (Lee et al, 1999). Truncations of this plasmid have been constructed by PCR and recombinant cloning techniques.…”

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.…”