Abstract
In primary cells, overexpression of oncogenes such as Ras(V12) induces premature senescence rather than transformation. Senescence is an irreversible form of G1 arrest that requires the p19ARF/p53 and p16INK4a/pRB pathways and may suppress tumorigenesis in vivo. Here we show that the transcription factor C/EBPbeta is required for Ras(V12)-induced senescence. C/EBPbeta-/- mouse embryo fibroblasts (MEFs) expressing Ras(V12) continued to proliferate despite unimpaired induction of p19ARF and p53, and lacked morphological features of senescent fibroblasts. Enforced C/EBPbeta expression inhibited proliferation of wild-type MEFs and also slowed proliferation of p19Arf-/- and p53-/- cells, indicating that C/EBPbeta acts downstream or independently of p19ARF/p53 to suppress growth. C/EBPbeta was unable to inhibit proliferation of MEFs lacking all three RB family proteins or wild-type cells expressing dominant negative E2F-1 and, instead, stimulated their growth. C/EBPbeta decreased expression of several E2F target genes and was associated with their promoters in chromatin immunoprecipitation assays, suggesting that C/EBPbeta functions by repressing genes required for cell cycle progression. C/EBPbeta is therefore a novel component of the RB:E2F-dependent senescence program activated by oncogenic stress in primary cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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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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CCAAT-Enhancer-Binding Proteins / deficiency
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Cycle*
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Cells, Cultured
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Cellular Senescence / physiology*
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / genetics
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E2F Transcription Factors
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E2F1 Transcription Factor
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Mice
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Mice, Knockout
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Promoter Regions, Genetic / genetics
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Rats
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Retinoblastoma Protein / deficiency
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Transcription Factor CHOP
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p14ARF / deficiency
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / metabolism
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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CCAAT-Enhancer-Binding Proteins
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Cdkn2a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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Ddit3 protein, mouse
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Ddit3 protein, rat
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2f1 protein, mouse
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E2f1 protein, rat
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Retinoblastoma Protein
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Transcription Factor CHOP
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ras Proteins