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

Ricky W. Johnstone, Raymond H. See, Stephen F. Sells, Jing Wang, Sumathi Muthukkumar, Christoph Englert, Daniel A. Haber, Jon D. Light, Stephen P. Sugrue, Tom Roberts, Vivek M. Rangnekar, Yang Shi

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

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 nut by the related protein EGRI. 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 in 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.

Original languageEnglish
Pages (from-to)6945-6956
Number of pages12
JournalMolecular and Cellular Biology
Volume16
Issue number12
DOIs
StatePublished - 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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