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C/EBPβ cooperates with RB:E2F to implement Ras V12 ‐induced cellular senescence
Author(s) -
Sebastian Thomas,
Malik Radek,
Thomas Sara,
Sage Julien,
Johnson Peter Frederick
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600789
Subject(s) - biology , senescence , carcinogenesis , e2f , cell growth , microbiology and biotechnology , transcription factor , chromatin immunoprecipitation , cell cycle , retinoblastoma protein , gene expression , promoter , gene , genetics
In primary cells, overexpression of oncogenes such as Ras V12 induces premature senescence rather than transformation. Senescence is an irreversible form of G 1 arrest that requires the p19 ARF /p53 and p16 INK4a /pRB pathways and may suppress tumorigenesis in vivo . Here we show that the transcription factor C/EBPβ is required for Ras V12 ‐induced senescence. C/EBP β −/− mouse embryo fibroblasts (MEFs) expressing Ras V12 continued to proliferate despite unimpaired induction of p19 ARF and p53, and lacked morphological features of senescent fibroblasts. Enforced C/EBPβ expression inhibited proliferation of wild‐type MEFs and also slowed proliferation of p19 Arf−/− and p53 −/− cells, indicating that C/EBPβ acts downstream or independently of p19 ARF /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.