Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence / genetics
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Binding Sites / genetics
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Cell Cycle Proteins / genetics
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Cell Differentiation / genetics*
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Cell Division / genetics*
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Cells, Cultured
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DEAD Box Protein 20
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DEAD-box RNA Helicases
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Fungal Proteins*
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Genes, cdc / physiology
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Guinea Pigs
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Immune System / growth & development*
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Immune System / metabolism*
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Macrophages / metabolism*
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Molecular Sequence Data
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Promoter Regions, Genetic / genetics
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Protein Structure, Tertiary / genetics
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Proteins*
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RNA Helicases / genetics
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Rats
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Repressor Proteins / genetics*
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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Serine Endopeptidases / deficiency
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Serine Endopeptidases / genetics
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Signal Transduction / genetics*
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Transcription Factors*
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ras Proteins / genetics*
Substances
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Cell Cycle Proteins
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ETV3 protein, mouse
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Fungal Proteins
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Nuclear Proteins
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Phosphoproteins
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Proteins
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Rbl1 protein, mouse
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Rbl2 protein, rat
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Repressor Proteins
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Retinoblastoma-Like Protein p107
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Retinoblastoma-Like Protein p130
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Transcription Factors
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Serine Endopeptidases
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DEAD Box Protein 20
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Ddx20 protein, mouse
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DEAD-box RNA Helicases
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RNA Helicases
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ras Proteins
Associated data
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GENBANK/AF155803
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GENBANK/AF217000
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GENBANK/AF217001
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GENBANK/AF218539
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GENBANK/AF218540