Repression of the Insulin-Like Growth Factor II Gene by the Wilms Tumor Suppressor WT1

Abstract

The Wilms tumor suppressor gene wt1 encodes a zinc finger DNA binding protein, WT1, that functions as a transcriptional repressor. The fetal mitogen insulin-like growth factor II (IGF-II) is overexpressed in Wilms tumors and may have autocrine effects in tumor progression. The major fetal IGF-II promoter was defined in transient transfection assays as a region spanning from nucleotides -295 to +135, relative to the transcription start site. WT1 bound to multiple sites in this region and functioned as a potent repressor of IGF-II transcription in vivo. Maximal repression was dependent on the presence of WT1 binding sites on each side of the transcriptional initiation site. These findings provide a molecular basis for overexpression of IGF-II in Wilms tumors and suggest that WT1 negatively regulates blastemal cell proliferation by limiting the production of a fetal growth factor in the developing vertebrate kidney.

Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program

“…Reported target genes for the WT1 protein include both genes involved in growth regulation and genes necessary for induction of di erentiation, such as c-myc, bcl-2 (Hewitt et al, 1995), colony-stimulating factor-1 (CSF-1) (Harrington et al, 1993), transforming growth factor-b1 (TGF-b1) (Dey et al, 1994), insulin-like growth factor 1 receptor (IGF1R) (Werner et al, 1993), insulin-like growth factor II (IGF II) (Drummond et al, 1992), platelet-derived growth factor A-chain (PDGF-A) (Gashler et al, 1992) and retinoic acid receptor-a (RAR-a) (Goodyer et al, 1995). The WT1 protein has been shown to mediate either transcriptional repression or activation, depending on the architecture of the promoter under study and the cell lines in which the transfection assay were performed (Madden et al, , 1993Drummond et al, 1992;Maheswaran et al, 1993;Werner et al, 1993;Wang et al, 1993b).…”

Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms' tumor

“…(2) Twothirds of Wilms' tumors maintaining heterozygosity at the IGF2 locus show relaxation of imprinting (Rainier et al, 1993;Ogawa et al, 1993a), allowing expression of both copies, and this is also seen constitutionally in the Beckwith-Wiedemann syndrome (Weksberg et al, 1993). (3) The WT1 gene, whose inactivation accounts for some Wilms' tumors, encodes a zinc-®nger protein that, in vitro, represses expression of IGF-II (Drummond et al, 1992) and of its mitogenic receptor (Werner et al, 1993). The diversity of the molecular abnormalities that can cause increased IGF2 dosage in Wilms' tumor makes it unlikely that it is a mere embryonal marker.…”

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

“…Several G\C box-binding transcription factors have been identified that are involved in P3 regulation via this proximal region. The product of the Wilms' tumour suppressor gene, WT1, is able to repress P3 by binding to different sites in the promoter and within exon 5 [10]. Another factor that binds the same site as WT1, EGR-1, is able to stimulate P3 [11].…”