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WT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells
1Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Abstract:
The Wilms' tumor suppressor gene WT1 encodes a zinc finger transcription factor, whose expression inhibits the growth of the RM1 Wilms' tumor cell line. Transient transfection of WT1 constructs into 3T3 or 293 cells results in transcriptional repression of a number of cotransfected promoters containing the early growth response gene 1 consensus sequence. We now show that WT1 has properties of a transcriptional activator in RM1 cells, an effect that may be associated with the presence of a mutated p53 gene in these cells. Stable transfection of wild-type WT1 into RM1 cells results in induction of endogenous insulin-like growth factor 2 (IGF2) but not of other previously postulated WT1-target genes. The induction of IGF2 is dramatically enhanced by WT1 mutants encoding an altered transactivation domain. We conclude that IGF2 is a potentially physiological target gene for WT1 and that its induction may contribute to the growth-stimulating effects of WT1 variants.
Insights
The Wilms' tumor suppressor gene WT1 acts as a transcriptional activator in RM1 cells, unlike its inhibitory role elsewhere. It specifically induces insulin-like growth factor 2 (IGF2), suggesting a role in tumor growth.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Gene Regulation
Background:
- The Wilms' tumor suppressor gene WT1 encodes a transcription factor with known growth-inhibitory functions.
- WT1's role in gene regulation can vary depending on cellular context and mutations.
Purpose of the Study:
- To investigate the transcriptional activity of WT1 in the RM1 Wilms' tumor cell line.
- To identify potential target genes regulated by WT1 in this specific cellular context.
Main Methods:
- Transient and stable transfection of WT1 constructs into cell lines (3T3, 293, RM1).
- Analysis of transcriptional activity on cotransfected promoters.
- Assessment of endogenous gene expression, including insulin-like growth factor 2 (IGF2).
Main Results:
- WT1 exhibits transcriptional activating properties in RM1 cells, potentially linked to mutated p53.
- Stable WT1 expression induces endogenous IGF2 in RM1 cells.
- WT1 mutants with altered transactivation domains enhance IGF2 induction.
Conclusions:
- Insulin-like growth factor 2 (IGF2) is identified as a potential physiological target gene of WT1.
- WT1-mediated induction of IGF2 may contribute to growth-stimulating effects of WT1 variants in certain cancers.