Mammalian Mip/Lin-9 Interacts With Either The P107, P130/E2f4 Repressor Complex Or B-Myb In A Cell Cycle-Phase-Dependent Context Distinct From The Drosophila Dream Complex

Mammalian Mip/LIN-9 is a cell cycle regulatory protein that is negatively regulated by CDK4/cyclin D. It has been demonstrated that Mip/LIN-9 collaborates with B-Myb during S and G2/M in the induction of cyclins A and B, and CDK1. The ortholog of Mip/LIN-9 in (D) under bar rosophila, Mip130, is part of a large multisubunit protein complex that includes (R) under bar BF, repressor (E) under bar 2Fs (a) under bar nd (M) under bar yb, in what was termed the dREAM complex. A similar complex, although lacking B-Myb, was also described in Caenorhabditis elegans. Here, we demonstrate that unlike Drosophila, Mip/LIN-9 has mutually exclusive and cell cycle-phasespeci. c interactions with the mammalian orthologs of the dREAM complex. In G(0)/early G(1), Mip/LIN-9 forms a complex with E2F4 and p107 or p130, while in late G(1)/S phase, it associates with B-Myb. The separation of Mip/LIN-9 from p107, p130/E2F4 is likely driven by phosphorylation of the pocket proteins by CDK4 since Mip/LIN-9 fails to interact with phosphorylated forms of p107, p130. Importantly, the repressor complex that Mip/LIN-9 forms with p107 takes functional precedence over the transcriptional activation linked to the Mip/LIN-9 and B-Myb interaction since expression of p107 blocks the activation of the cyclin B promoter triggered by B-Myb and Mip/LIN-9.