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Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1

I A Drummond1, S L Madden, P Rohwer-Nutter

  • 1Howard Hughes Medical Institute, University of Chicago, IL 60637.

Science (New York, N.Y.)
|July 31, 1992
PubMed

Insights

The Wilms tumor suppressor gene WT1 acts as a repressor, controlling insulin-like growth factor II (IGF-II) transcription. This finding explains IGF-II overexpression in Wilms tumors and WT1's role in kidney development.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Genetics

Background:

  • Wilms tumor is a pediatric kidney cancer often associated with overexpression of insulin-like growth factor II (IGF-II), a fetal mitogen.
  • The Wilms tumor suppressor gene (WT1) encodes a transcription factor that typically acts as a repressor.

Purpose of the Study:

  • To investigate the molecular mechanism by which WT1 regulates IGF-II transcription.
  • To determine if WT1 directly represses the IGF-II promoter and its role in Wilms tumor pathogenesis.

Main Methods:

  • Transient transfection assays were used to define the major fetal IGF-II promoter region.
  • WT1 binding to the IGF-II promoter was assessed in vivo.
  • Reporter gene assays were employed to measure WT1's repressive activity on IGF-II transcription.

Main Results:

  • The major fetal IGF-II promoter was mapped to a region from nucleotides -295 to +135.
  • WT1 was found to bind to multiple sites within this promoter region.
  • WT1 demonstrated potent repression of IGF-II transcription in vivo, with maximal repression dependent on WT1 binding sites flanking the transcription start site.

Conclusions:

  • WT1 directly represses the major fetal IGF-II promoter, providing a molecular explanation for IGF-II overexpression in Wilms tumors.
  • WT1 negatively regulates blastemal cell proliferation by limiting IGF-II production during kidney development.
  • These findings highlight a critical regulatory axis in kidney development and Wilms tumorigenesis.

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