Tumor-associated WT1 missense mutants indicate that transcriptional activation by WT1 is critical for growth control

The WT1 gene encodes a zinc finger DNA binding transcription factor and is mutated in up to 15% of Wilms tumor cases. The WT1 protein binds to the pro moters of many genes through GC- or TC-rich sequences and can function both as a transcriptional repressor and an activator in co-transfection assays depending on the cell type, the structure of the test promoter, and even th e expression vectors used. Engineered expression of WT1 can lead to growth suppression by both cell cycle arrest and induction of apoptosis. However, the transcriptional activity of WT1 that is required for growth control was not defined. We found that three N-terminal tumor-associated missense muta tions of WT1 were defective for activation of both a synthetic reporter con taining WT1-binding sites as well as the promoter of a WT1 responsive gene, p21. These mutants failed to inhibit cell growth but still retain their ab ility to repress several putative WT1 target promoters. These results indic ate that activation and not repression by WT1 is the critical transcription al activity of the protein responsible for its growth suppressing propertie s.