RBP1 Recruits Both Histone Deacetylase-Dependent and -Independent Repression Activities to Retinoblastoma Family Proteins

Abstract

Retinoblastoma (RB) tumor suppressor family proteins block cell proliferation in part by repressing certain E2F-specific promoters. Both histone deacetylase (HDAC)-dependent and -independent repression activities are associated with the RB “pocket.” The mechanism by which these two repression functions occupy the pocket is unknown. A known RB-binding protein, RBP1, was previously found by our group to be an active corepressor which, if overexpressed, represses E2F-mediated transcription via its association with the pocket. We show here that RBP1 contains two repression domains, one of which binds all three known HDACs and represses them in an HDAC-dependent manner while the other domain functions independently of the HDACs. Thus, RB family members repress transcription by recruiting RBP1 to the pocket. RBP1, in turn, serves as a bridging molecule to recruit HDACs and, in addition, provides a second HDAC-independent repression function.

ACKNOWLEDGMENTS

We thank Tony Kouzarides for Gal4-pRB(pocket) and for helpful discussions; Xiang-Jiao Yang and Brian Kennedy for critical review of the manuscript; Arnie Berk for Gal4-VP16, pSG424, and G5TKCAT; and Doug Dean and Don Ayer for G5MLPCAT and G5SV40CAT. We also thank Dennis Paquette for the construction of the Gal4-RBP1dl-R1 mutant.

This work was supported through grants from the National Cancer Institute of Canada and the Medical Research Council of Canada.