Transcriptional activity of testis-determining factor SRY is modulated by the Wilms' tumor 1 gene product, WT1

Oncogene. 2003 Sep 11;22(39):7900-4. doi: 10.1038/sj.onc.1206717.

Abstract

The Wilms' tumor 1 (WT1) and sex-determining region of the Y chromosome (SRY) genes are essential for development of the mammalian gonads and mutations in these genes are associated with gonadal dysgenesis in humans. The SRY gene encodes a transcription factor with one high-mobility group (HMG) box as a DNA-binding domain. WT1 encodes a transcription factor that contains four contiguous C2H2-type zinc-finger motifs as a DNA/RNA binding or protein-protein interaction domain. Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites. This interaction is mediated by the WT1 zinc-finger domain and the SRY HMG box. WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY. Wildtype WT1 is recruited to SRY-binding sites in an SRY-dependent manner, whereas DDS mutants are not recruited as efficiently. These results suggest that WT1 forms a complex with SRY to regulate transcription and that this WT1-SRY interaction is important in testis development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Denys-Drash Syndrome / genetics
  • HMG-Box Domains
  • Humans
  • Male
  • Mutation
  • Nuclear Proteins*
  • Promoter Regions, Genetic
  • RNA Splicing Factors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Sex-Determining Region Y Protein
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / physiology*
  • WT1 Proteins / genetics
  • WT1 Proteins / metabolism*
  • Zinc Fingers

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • SF1 protein, human
  • SRY protein, human
  • Sex-Determining Region Y Protein
  • Transcription Factors
  • WT1 Proteins