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 lo ss and/or imbalance of the dual transcriptional activity of WT1 may co ntribute to Wilms' tumor, In this study, we identified par-4 (for pros tate apoptosis response) as a WT1-interacting protein that itself func tions as a transcriptional repressor, par-4 contains a putative leucin e zipper domain and is specifically upregulated during apoptosis of pr ostate cells (S. F. Sells, D. P. Wood, Jr., S. S. Joshi-Barve, S. Muth ukkumar, 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 WT 1, 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, Function ally, par-4 inhibited transcription activated by WT1, but not by the r elated protein EGR1, Inhibition of WT1-mediated transcription was depe ndent on the domain of par-4 that mediates its physical association wi th WT1. In addition, par-4 augmented WT1-mediated repression, possibly by contributing an additional repression domain, Consistent,vith thes e results, par-4 functioned as a transcriptional repressor when brough t to a promoter via a heterologous DNA binding domain, Significantly, par-4, but not a mutant unable to interact with WT1, rescued growth su ppression caused by WT1. Thus, we identified a novel repressor that mo dulates transcription as well as growth suppression functions of WT1.