Terminal differentiation of cells is often accompanied by repression of cellular proliferation, suggesting that there is a mechanism by which these cellular functions are coordinated. Macrophage differentiation is one model system in which this occurs; as macrophages differentiate, they also stop proliferating. Transcriptional regulation plays a key role in cell cycle progression as well as many differentiation processes. Ras stimulates cell cycle progression in part through Ets transcription factors that bind to cell cycle regulatory genes to activate their expression. Ets transcription factors also help to induce early macrophage differentiation. The activation of Ras signaling by M-CSF activates transcription of genes involved in differentiation through the coordinate expression of both Ets factors and AP-1. Other genes involved in cell cycle regulation involved the coordinate action of E2F-1 and Ets transcription factors. Mets is a factor related in sequence to Ets2 that is upregulated during macrophage differentiation. Increased expression of the Mets protein during macrophage differentiation allows the creation of heterodimers with DP103 to act as transcriptional repressors of cell cycle progression genes, recruiting corepressor to promoters they interact with. DP103 is a gene previously identified as an RNA helicase involved in RNA processing that interacts with EBNA factors from Epstein Barr Virus. The transcriptional repression involving Mets with DP103 is selective, and does not involve all Ets regulated genes. While cell cycle genes are repressed by Mets, other gene activated by Ets factors such as those involved in differentiation are not repressed by Mets. The transcriptional repression by Mets also involved members of the Rb family of tumor suppressors, such as p107 and p130. This requirement for additional factors involved in regulating proliferation may allow for another level of control on cell proliferation and coordination with differentiation.
