TRIP‐Br: a novel family of PHD zinc finger‐ and bromodomain‐interacting proteins that regulate the transcriptional activity of E2F‐1/DP‐1

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.