Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Ras-dependent proliferation without inhibiting Ras-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD box-containing protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation.
Pubmed ID: 12007404 RIS Download
Mesh terms: Animals | Base Sequence | Binding Sites | Cell Cycle Proteins | Cell Differentiation | Cell Division | Cells, Cultured | DEAD Box Protein 20 | DEAD-box RNA Helicases | Fungal Proteins | Genes, cdc | Guinea Pigs | Immune System | Macrophages | Molecular Sequence Data | Nuclear Proteins | Phosphoproteins | Promoter Regions, Genetic | Protein Structure, Tertiary | Proteins | RNA Helicases | Rats | Repressor Proteins | Retinoblastoma-Like Protein p107 | Retinoblastoma-Like Protein p130 | Serine Endopeptidases | Signal Transduction | Transcription Factors | ras Proteins
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