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C/EBP beta cooperates with RB : E2F to implement Ras(V12)-induced cellular senescence

  1. Author:
    Sebastian, T.
    Malik, R.
    Thomas, S.
    Sage, J.
    Johnson, P. F.

  2. Author Address

    NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA Johnson, PF, NCI, Lab Prot Dynam & Signaling, Bldg 539,Room 122,7th Mil St, Frederick, MD 21702 USA
    1. Year: 2005
    2. Date: SEP 21
  2. Journal: Embo Journal
    1. 24
    2. 18
    3. Pages: 3301-3312
  4. Type of Article: Article
  1. Abstract:

    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/EBP beta is required for Ras(V12)-induced senescence. C/EBP beta(-/-) 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/EBP beta expression inhibited proliferation of wild-type MEFs and also slowed proliferation of p19(Arf-/-) and p53(-/-) cells, indicating that C/EBP beta acts downstream or independently of p19(ARF)/p53 to suppress growth. C/EBP beta 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/EBP beta decreased expression of several E2F target genes and was associated with their promoters in chromatin immunoprecipitation assays, suggesting that C/EBP beta functions by repressing genes required for cell cycle progression. C/EBP beta is therefore a novel component of the RB: E2F-dependent senescence program activated by oncogenic stress in primary cells

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  1. View record in Web of Science®
  2. WOS: 000232551600014

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