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Keywords:

  • C/EBPβ;
  • cell cycle arrest;
  • cellular senescence;
  • oncogenic Ras;
  • RB:E2F

In primary cells, overexpression of oncogenes such as RasV12 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/EBPβ is required for RasV12-induced senescence. C/EBPβ−/− mouse embryo fibroblasts (MEFs) expressing RasV12 continued to proliferate despite unimpaired induction of p19ARF and p53, and lacked morphological features of senescent fibroblasts. Enforced C/EBPβ expression inhibited proliferation of wild-type MEFs and also slowed proliferation of p19Arf−/− and p53−/− cells, indicating that C/EBPβ acts downstream or independently of p19ARF/p53 to suppress growth. C/EBPβ 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/EBPβ decreased expression of several E2F target genes and was associated with their promoters in chromatin immunoprecipitation assays, suggesting that C/EBPβ functions by repressing genes required for cell cycle progression. C/EBPβ is therefore a novel component of the RB:E2F-dependent senescence program activated by oncogenic stress in primary cells.