Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle

Control of proliferation and differentiation by the retinoblastoma tumor su ppressor protein (pRB) and related family members depends upon their intera ctions with key cellular substrates. Efforts to identify such cellular targ ets led to the isolation of a novel protein, EID-1 (for E1A-like inhibitor of differentiation 1). Here, we show that EID-1 is a potent inhibitor of di fferentiation and link this activity to its ability to inhibit p300 land th e highly related molecule, CREB-binding protein, or CBP) histone acetylatio n activity. EID-1 is rapidly degraded by the proteasome as cells exit the c ell cycle. Ubiquitination of EID-1 requires an intact C-terminal region tha t is also necessary for stable binding to p300 and pRB, two proteins that b ind to the ubiquitin ligase MDM2. A pRB variant that can bind to EID1, but not MDM2, stabilizes EID-1 in cells. Thus, EID-1 may act at a nodal point t hat couples cell cycle exit to the transcriptional activation of genes requ ired for differentiation.