RETINOBLASTOMA PROTEIN DIRECTLY INTERACTS WITH AND ACTIVATES THE TRANSCRIPTION FACTOR NF-IL6

The biological function of the retinoblastoma protein (RB) in the cell division cycle has been extensively documented, but its apparent role in differentiation remains largely unexplored. To investigate how RB is involved in differentiation, the U937 large-cell lymphoma line was induced to differentiate along a monocyte/macrophage lineage, During d ifferentiation RB was found to interact directly through its simian vi rus 40 large tumor antigen (T antigen)-binding domain with NF-IL6, a m ember of the CAAT/enhancer-binding protein (C/EBP) family of transcrip tion factors. NF-IL6 utilizes two distinct regions to bind to the hypo phosphorylated form of RB in vitro and in cells. Wild-type but not mut ant RB enhanced both binding activity of NF-IL6 to its cognate DNA seq uences in vitro and promoter transactivation by NF-IL6 in cells. These findings indicate a novel biochemical function of RB: it activates, b y an apparent chaperone-like activity, specific transcription factors important for differentiation. This contrasts with its sequestration a nd inactivation of other transcription factors, such as E2F-1, which p romote progression of the cell cycle, Such disparate mechanisms may he lp to explain the dual role of RB in cell differentiation and the cell division cycle.