Binding of pRB to the PHD protein RBP2 promotes cellular differentiation.

pRB can enforce a G1 block by repressing E2F-responsive promoters. It also coactivates certain non-E2F transcription factors and promotes differentiation. Some pRB variants activate transcription and promote differentiation despite impaired E2F binding and transcriptional repression capabilities. We identified RBP2 in a screen for proteins that bind to such pRB variants. RBP2 resembles other chromatin-associated transcriptional regulators and RBP2 binding tracked with pRB's ability to activate transcription and promote differentiation. RBP2 and pRB colocalize and pRB/RBP2 complexes were detected in chromatin isolated from differentiating cells. RBP2 siRNA phenocopied restoration of pRB function in coactivation and differentiation assays, suggesting that pRB prevents RBP2 from repressing genes required for differentiation. In addition, two bromodomain-containing proteins were identified as RBP2 targets that are transcriptionally activated by pRB in an RBP2-dependent manner. Our results suggest that promotion of differentiation by pRB involves neutralization of free RBP2 and transcriptional activation of RBP2 targets linked to euchromatin maintenance.