INDUCTION OF RB-ASSOCIATED PROTEIN (RBAP46) BY WILMS-TUMOR SUPPRESSORWT1 MEDIATES GROWTH-INHIBITION

The Wilms' tumor suppressor gene, wt1, encodes a zinc-finger transcrip tion factor, WT1, that plays an important role in controlling urogenit al 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 tha t are transcriptionally activated by WT1 have been established. Using suppression subtractive hybridization polymerase chain reaction, we is olated a WT1 target gene that is up-regulated about 15-fold in cells e xpressing WT1. The gene was identified as retinoblastoma suppressor (R b)-associated protein 46 (RbAp46), a nuclear protein that interacts ph ysically with Rb and is a component of the human mSin3 co-repressor co mplex. Cells transfected with RbAp46 cDNA formed fewer colonies than t he control cells, and RbAp46 suppressed the growth rate (by about a-fo ld) of transfected cells. In the developing kidney and gonad, RbAp46 e xhibits an expression pattern similar to that of WT1. We conclude that RbAp46 has strong growth inhibition activity and may function as an i mportant mediator of WT1's function.