The Wilms' tumor suppressor gene WT1 is negatively autoregulated.

Rupprecht, Harald; Drummond, I A; Madden, S L; Rauscher, F. J.; Sukhatme, Vikas P.

doi:10.1016/s0021-9258(17)37588-9

Cited by 113 publications

(4 citation statements)

References 38 publications

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“…sequence and has been implicated in some aspect of RNA processing [7]. The presence or absence of 17 amino acids confirm the previously postulated autoregulation of WT1 thought to contribute to the formation of slit diaphragms via the separation of podocyte "foot processes", thereby expression (Figure 1b) [9]. We were also unable to confirm changes in the expression of a number of other previously allowing filtration of blood through the glomerulus [11,12].…”

Section: Wilms Tumor [2 3] Wt1 Target Genes Implicated In Cell Cycle Regulation and Cellular Proliferation Havecontrasting

confidence: 47%

WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin

et al. 2001

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The WT1 tumor suppressor gene encodes a zinc finger transcription factor expressed in differentiating glomerular podocytes. Complete inactivation of WT1 in the mouse leads to failure of mesenchymal induction and renal agenesis, an early developmental phenotype that prevents analysis of subsequent stages in glomerular differentiation [1]. In humans with Denys-Drash Syndrome, a heterozygous germline mutation in WT1 is associated with specific defects in glomeruli and an increased risk for developing Wilms Tumor [2,3]. WT1 target genes implicated in cell cycle regulation and cellular proliferation have been proposed [4], but the link between WT1 function and glomerular differentiation is unexplained. Here, we show that inducible expression of WT1 in rat embryonic kidney cell precursors leads to the induction of endogenous Podocalyxin, the major structural membrane protein of glomerular podocytes, which is implicated in the maintenance of filtration slits. Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. These observations support a role for WT1 in the specific activation of a glomerular differentiation program in renal precursors and provide a molecular basis for the glomerulonephropathy that is characteristic of Denys-Drash Syndrome.

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Section: Wilms Tumor [2 3] Wt1 Target Genes Implicated In Cell Cycle Regulation and Cellular Proliferation Havecontrasting

confidence: 47%

WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin

et al. 2001

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“…It has been demonstrated previously that WT1 binds with similar affinity to DNA sequences containing the consensus site for the EGR1 protein ( , ). Furthermore, in transient transfection assays both proteins can regulate promoters containing such sequences, with EGR1 activating transcription and WT1 repressing transcription ( − ). On the basis of these results, it has been suggested that WT1 and EGR1 may act as antagonists in developmental regulation of transcription.…”

Section: Discussionmentioning

confidence: 99%

“…The results of a number of transient transfection studies demonstrated that WT1 represses transcription of promoters responsive to EGR-1 ( − ). These results suggest that there may be a regulatory link between these two proteins: WT1 may act as an antagonist of EGR1 or may be a tissue-specific factor that is involved in maintaining a particular differentiated phenotype.…”

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confidence: 99%

Comparison of the DNA Binding Characteristics of the Related Zinc Finger Proteins WT1 and EGR1

1998

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The interactions of the related zinc finger proteins WT1 and EGR1 with DNA have been investigated using a quantitative binding assay. A recombinant peptide containing the four zinc fingers of WT1 binds to the dodecamer DNA sequence GCG-TGG-GCG-TGT with an apparent dissociation constant (Kd) of (1.14 +/- 0.09) x 10(-9) M under conditions of 0.1 M KCl, pH 7.5, at 22 degrees C. Under the same conditions, a recombinant peptide containing the three zinc fingers of EGR1 binds to the dodecamer sequence, the first nine bases comprising the EGR consensus binding site, with an apparent Kd of (3.55 +/- 0.24) x 10(-9) M. The nature of the equilibrium binding of each peptide to DNA was investigated as a function of temperature, pH, monovalent salt concentration, and divalent salt concentration. The interaction of WT1 with DNA is an entropy-driven process, while the formation of the EGR1-DNA complex is favored by enthalpy and entropy. The DNA binding activities of both proteins have broad pH optima centered at pH 8.0. The binding of both proteins to DNA shows similar sensitivity to ionic strength, with approximately 7.7 +/- 0.8 ion pairs formed in the EGR1-DNA complex and 9.2 +/- 1.8 ion pairs formed in the WT1-DNA complex. Results of measuring the effects of point mutations in the DNA binding site on the affinity of WT1 and EGR1 indicates a significant difference in the optimal binding sites: for EGR1, the highest affinity binding site has the sequence GNG-(T/G)GG-G(T/C)G, while for WT1 the highest affinity binding site has the sequence G(T/C)G-(T/G)GG-GAG-(T/C)G(T/C).

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“…gene expression [31]. To date, retinoic acid [18], PAX2 [32], PAX8 [32], Sp-1 [33], NF-jB [34], GATA-1 [35], GATA-2 [35] and WT1 itself [22,36] are known to interact with a promoter or an enhancer region of the WT1 gene and modulate WT1 gene expression. In this study, we showed, using a reporter assay, that TGF-beta1 reduced activity of a 5# enhancer of the WT1 gene, while it did not alter the promoter activity.…”

Section: Discussionmentioning

confidence: 99%