Journal of Biological Chemistry
Volume 271, Issue 32, 9 August 1996, Pages 19304-19309
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Nucleic Acids, Protein Synthesis, and Molecular Genetics
The IGF-I Receptor Gene Promoter Is a Molecular Target for the Ewing's Sarcoma-Wilms' Tumor 1 Fusion Protein*

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Desmoplastic small round cell tumor (DSRCT) is an abdominal malignancy in children which is characterized by a recurrent chromosomal translocation, t(11;22)(p13;q12). This rearrangement results in the fusion of the ubiquitously expressed EWS1 gene to the Wilms' tumor suppressor (WT1) gene. The chimeric protein contains the N-terminal domain of EWS1 fused to the DNA-binding domain of WT1, including zinc fingers 2-4. Because WT1 has been shown previously to bind and repress the insulin-like growth factor I (IGF-I-R) promoter, we investigated whether this promoter is, in addition, a target for the aberrant EWS/WT1 transcription factor.

EWS/WT1 activated the IGF-I-R promoter ~340%, whereas a fusion protein containing a three-amino acid insert (KTS) between zinc fingers 3 and 4 had no effect. On the other hand, expression vectors encoding either WT1 or EWS1 reduced the activity of the promoter to 46 and 58% of control values, respectively. Results of gel shift assays indicate that the binding affinity of EWS/WT1 to a fragment of the 5′-flanking region of the receptor promoter was higher than the affinity of WT1 itself. Consistent with the results of functional assays, the binding of EWS/WT1(+KTS) was significantly reduced. Due to the central role of the IGF-I-R in tumorigenesis, activation of the receptor promoter by EWS/WT1 may constitute a potential mechanism for the etiology and/or progression of DSRCT.

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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by National Institutes of Health Grant CA52009, Core Grant CA10815, and Grant DK49210, the Irving A. Hansen Memorial Foundation, the Mary A. Rumsey Memorial Foundation, and the Pew Scholars Program in the Biomedical Sciences.