Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression

Haim Werner, Zila Shen-Orr, Frank J. Rauscher, Jennifer F. Morris, Charles T. Roberts, Derek LeRoith

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    Abstract

    We have investigated the regulation of the insulin-like growth factor I receptor (IGF-I-R) gene promoter by the Wilms' tumor suppressor WT1 in intact cells. The levels of endogenous IGF-I-R mRNA and the activity of IGF-I-R gene promoter fragments in luciferase reporter constructs were found to be significantly higher in G401 cells (a Wilms' tumor-derived cell line lacking detectable WT1 mRNA) than in 293 cells (a human embryonic kidney cell line which expresses significant levels of WT1 mRNA). To study whether WT1 could suppress the expression of the endogenous IGF-I-R gene, WT1-negative G401 cells were stably transfected with a WT1 expression vector. Expression of WT1 mRNA in G401 cells resulted in a significant decrease in the rate of cellular proliferation, which was associated with a reduction in the levels of IGF-I- R mRNA, promoter activity, and ligand binding and with a reduction in IGF-I- stimulated cellular proliferation, thymidine incorporation, and anchorage- independent growth. These data suggest that a major aspect of the action of the WT1 tumor suppressor is the repression of IGF-I-R gene expression.

    Original languageEnglish (US)
    Pages (from-to)3516-3522
    Number of pages7
    JournalMolecular and cellular biology
    Volume15
    Issue number7
    DOIs
    StatePublished - Jul 1995

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    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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