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A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1.

The tumor suppressor WT1 represses and activates transcription. The loss and/or imbalance of the dual transcriptional activity of WT1 may contribute to Wilms' tumor. In this study, we identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. par-4 contains a putative leucine zipper domain and is specifically upregulated during apoptosis of prostate cells (S. F. Sells, D. P. Wood, Jr., S. S. Joshi-Barve, S. Muthukkumar, R. J. Jacob, S. A. Crist, S. Humphreys, and V. M. Rangnekar, Cell Growth Differ. 5:457-466, 1994). The leucine repeat domain of par-4 was shown to interact with the zinc finger DNA binding domain of WT1. Immunoprecipitation-Western blot (immunoblot) analyses demonstrated in vivo WT1-par-4 interactions. par-4 was ubiquitously expressed, and the protein was found in both the nucleus and the cytoplasm. Functionally, par-4 inhibited transcription activated by WT1, but not by the related protein EGR1. Inhibition of WT1-mediated transcription was dependent on the domain of par-4 that mediates its physical association with WT1. In addition, par-4 augmented WT1-mediated repression, possibly by contributing an additional repression domain. Consistent with these results, par-4 functioned as a transcriptional repressor when brought to a promoter via a heterologous DNA binding domain. Significantly, par-4, but not a mutant unable to interact with WT1, rescued growth suppression caused by WT1. Thus, we identified a novel repressor that modulates transcription as well as growth suppression functions of WT1.

Pubmed ID: 8943350


  • Johnstone RW
  • See RH
  • Sells SF
  • Wang J
  • Muthukkumar S
  • Englert C
  • Haber DA
  • Licht JD
  • Sugrue SP
  • Roberts T
  • Rangnekar VM
  • Shi Y


Molecular and cellular biology

Publication Data

December 31, 1996

Associated Grants

  • Agency: NCI NIH HHS, Id: CA60872
  • Agency: NCI NIH HHS, Id: CA68258

Mesh Terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Genes, Wilms Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Repressor Proteins
  • Sequence Alignment
  • Transcription Factors
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • WT1 Proteins