Abstract
In the absence of growth signals, cells exit the cell cycle and enter into G0 or quiescence. Alternatively, cells enter senescence in response to inappropriate growth signals such as oncogene expression. The molecular mechanisms required for cell cycle exit into quiescence or senescence are poorly understood. The DREAM (DP, RB [retinoblastoma], E2F, and MuvB) complex represses cell cycle-dependent genes during quiescence. DREAM contains p130, E2F4, DP1, and a stable core complex of five MuvB-like proteins: LIN9, LIN37, LIN52, LIN54, and RBBP4. In mammalian cells, the MuvB core dissociates from p130 upon entry into the cell cycle and binds to BMYB during S phase to activate the transcription of genes expressed late in the cell cycle. We used mass spectroscopic analysis to identify phosphorylation sites that regulate the switch of the MuvB core from BMYB to DREAM. Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly. Inhibiting DYRK1A activity or point mutation of LIN52 disrupts DREAM assembly and reduces the ability of cells to enter quiescence or undergo Ras-induced senescence. These data reveal an important role for DYRK1A in the regulation of DREAM activity and entry into quiescence.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Line
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Cell Line, Tumor
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Cell Proliferation
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Cells, Cultured
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Cellular Senescence / genetics
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Cellular Senescence / physiology*
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Dyrk Kinases
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E2F4 Transcription Factor / genetics
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E2F4 Transcription Factor / metabolism
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Humans
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Mice
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NIH 3T3 Cells
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Retinoblastoma-Binding Protein 4 / genetics
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Retinoblastoma-Binding Protein 4 / metabolism
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Retinoblastoma-Like Protein p130 / genetics
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Retinoblastoma-Like Protein p130 / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factor DP1 / genetics
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Transcription Factor DP1 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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E2F4 Transcription Factor
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LIN-9 protein, mouse
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LIN9 protein, human
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Lin37 protein, human
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Lin54 protein, human
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Nuclear Proteins
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Retinoblastoma-Binding Protein 4
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Retinoblastoma-Like Protein p130
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Trans-Activators
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Transcription Factor DP1
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Tumor Suppressor Proteins
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases