Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition

The Wilms' tumor suppressor gene, wt1, encodes a zinc-finger transcription factor, WT1, that plays an important role in controlling urogenital development. Previously, WT1 has been shown to inhibit cell growth and to repress transcription initiated from the promoters of a number of growth-promoting genes. However, few physiological target genes that are transcriptionally activated by WT1 have been established. Using suppression subtractive hybridization polymerase chain reaction, we isolated a WT1 target gene that is up-regulated about 15-fold in cells expressing WT1. The gene was identified as retinoblastoma suppressor (Rb)-associated protein 46 (RbAp46), a nuclear protein that interacts physically with Rb and is a component of the human mSin3 co-repressor complex. Cells transfected with RbAp46 cDNA formed fewer colonies than the control cells, and RbAp46 suppressed the growth rate (by about a-fold) of transfected cells. In the developing kidney and gonad, RbAp46 exhibits an expression pattern similar to that of WT1. We conclude that RbAp46 has strong growth inhibition activity and may function as an important mediator of WT1's function.