Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions

The WT1 gene, which is heterozygously mutated or deleted in congenital anom aly syndromes and homozygously mutated in about 15% of all Wilms tumors, en codes tissue-specific developmental regulators. Through alternative mRNA sp licing, four main WT1 protein isoforms are synthesized, All isoforms can bi nd to DNA via their zinc fingers, albeit with different affinities and spec ificities, and thereby modulate the transcriptional activity of their targe t genes. Several proteins bind to and alter the transcription regulatory pr operties of the WT1 proteins, including the product of the tumor suppressor gene p53, interaction between WT1 and p53 was shown to modulate their abil ity to regulate the transcription of their respective target genes. Here, w e report that all four isoforms of WT1 bind to p73, a recently cloned homol ogue of p53, p73 binds to the zinc finger region of WT1 and thereby inhibit s DNA binding and transcription activation by WT1. Similarly, WT1 inhibits p73-induced transcription activation in reporter assays and counteracts p73 -induced expression of endogenous Mdm2. This, taken together with our findi ng that WT1 also interacts with p63/KET, another p53 homologue, suggests th at association between WT1 and the members of the p53 family of proteins ma y be an important determinant of their functions in cell growth and differe ntiation.