A functional interaction with CBP contributes to transcriptional activation by the Wilms tumor suppressor WT1

The Wilms tumor gene WT1 encodes a zinc finger transcription factor that is required for normal kidney development. WT1 was identified as a transcript ional repressor, based on its suppression of promoter reporters, but analys is of native transcripts using high density microarrays has uncovered trans criptional activation, rather than repression, of potential target genes. W e report here that WT1 binds to the transcriptional coactivator CBP, leadin g to synergistic activation of a physiologically relevant promoter. The phy sical interaction between WT1 and CBP is evident in vitro and in vivo, and the two proteins are co-immunoprecipitated from embryonic rat kidney cells. The WT1-CBP association requires the first two zinc fingers of WT1 and the adenovirus 5 E1A-binding domain of CBP. Overexpression of this domain of C BP is sufficient to inhibit WT1-mediated transcriptional activation of a pr omoter reporter, as is co-transfection of Elk Retrovirally driven expressio n of either the CBP fragment or of E1A in human hematopoietic cells suppres ses the induction by WT1 of its endogenous target gene, p21(Cip1). These ob servations support a model of WT1 as a transcriptional activator of genes r equired for cellular differentiation.