We report the isolation of TRIP-Br1, a transcriptional regulator that interacts with the PHD-bromodomain of co-repressors of Krüppel-associated box (KRAB)-mediated repression, KRIP-1 (TIF1β) and TIF1α, as well as the co-activator/adaptor p300/CBP. TRIP-Br1 and the related protein TRIP-Br2 possess transactivation domains. Like MDM2, which has a homologous transactivation domain, TRIP-Br proteins functionally contact DP-1, stimulating E2F-1/DP-1 transcriptional activity. KRIP-1 potentiates TRIP-Br protein co-activation of E2F-1/DP-1. TRIP-Br1 is a component of a multiprotein complex containing E2F-1 and DP-1. Co-expression of the retinoblastoma gene product (RB) abolishes baseline E2F-1/DP-1 transcriptional activity as well as TRIP-Br/KRIP-1 co-activation, both of which are restored by the adenovirus E1A oncoprotein. These features suggest that TRIP-Br proteins function at E2F-responsive promoters to integrate signals provided by PHD-and/or bromodomain-containing transcription factors. TRIP-Br1 is identical to the cyclin-dependent kinase 4 (cdk4)-binding protein p34 SEI-1, which renders the activity of cyclin D/cdk4 resistant to the inhibitory effect of p16 INK4a during late G 1. TRIP-Br1 (p34 SEI-1) is differentially overexpressed during the G 1 and S phases of the cell cycle, consistent with a dual role for TRIP-Br1 (p34 SEI-1) in the regulation of cell cycle progression through sequential effects on the transcriptional activity of E2F-responsive promoters during G 1 and S phases.