Transcriptional Repression Mediated by the WT1 Wilms Tumor Gene Product

Madden, Stephen L.; Cook, Donna; Morris, Jennifer; Gashler, Andrea; Sukhatme, Vikas P.; Rauscher, Frank J.

doi:10.1126/science.1654597

Cited by 468 publications

(337 citation statements)

References 21 publications

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“…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]. In addition to the TATA box, we have identified four other regions in the proximal region that were bound by nuclear factors from HeLa or Hep3B cells in footprinting experiments.…”

Section: Introductionmentioning

confidence: 92%

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

Rietveld

Holthuizen

Sussenbach

1997

Biochemical Journal

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Transcription of the human insulin-like growth factor II (IGF-II) gene is under the control of four promoters (P1-P4) that are differentially active during growth and development. Promoter 3 (P3) is the most active promoter during fetal development as well as in most adult tissues. P3 is also the most active promoter in tumour tissues and cell lines expressing IGF-II. Transient transfections of HeLa and Hep3B cells with truncated promoter constructs revealed that the region between -289 and -183 relative to the transcription start site supports basal promoter activity in both cell lines. Footprint experiments showed that the region between positions -192 and -172 (P3-4) is the only element bound by nuclear proteins. P3-4 is bound by five proteins, of which three proteins (proteins 3, 4 and 5) bind specifically and are expressed at the same levels in HeLa and Hep3B cells. Electrophoretic mobility shift assays and differential footprint experiments revealed the presence of two protein-binding regions within the P3-4 element. Proteins 4 and 5 bind box A (-193 to -188), whereas box B (-183 to -172) is bound by protein 3. From transcription experiments in vitro it can be concluded that Box A is essential for P3 activity. Box A is part of a region 11 dG residues long and is protected by proteins 4 and 5 that bind a contiguous set of six dG residues. DNA-binding of proteins 4 and 5 to box A requires the presence of Zn2+ ions. Thus structural and functional analysis reveals that the P3-4 element is a key regulatory element of P3 that contains two separate binding sites for proteins essential for the basal activity of IGF-II P3.

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Section: Introductionmentioning

confidence: 92%

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

Rietveld

Holthuizen

Sussenbach

1997

Biochemical Journal

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“…This construct contains the DNA-binding domain of Egr-1 fused to a transcriptional repression domain found in WT1 (Madden et al, 1991). As shown in Figure 6a, co-transfection of the dominant negative construct with the bFGF-luciferase reporter blocked the transcriptional activation of this reporter in response to stimulation with bFGF.…”

Section: Functional Analysis Of the Bfgf Promotermentioning

confidence: 97%

Basic fibroblast growth factor transcriptional autoregulation requires EGR-1

1997

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“…Although we have yet to discover an extinguisher that acts as a repressor of transcription, the recent characterization of the WT1 Wilms' tumor gene product, which functions in the developing kidney as a tissue-specific direct transcriptional repressor of genes that are activated by the mitogen-inducible factor EGR-1 (Ref. 29 The question of what regulates the regulator is particularly interesting because of the dominant action of extinguisher loci. For example, the transcriptional activity of the RIodTSE1 gene in human fibroblasts is preserved when the chromosome 17 on which it is carried is transferred by microcell fusion into the nucleus of a hepatoma cell that expresses RItz/TSE1 at a very low level z4.…”

Section: Figi~mentioning

confidence: 99%