C/EBPβ cooperates with RB:E2F to implement RasV12‐induced cellular senescence

Laboratory of Protein Dynamics and Signaling, NCI-Frederick, Frederick, MD 21702-1201, USA.
The EMBO Journal (Impact Factor: 10.43). 10/2005; 24(18):3301-12. DOI: 10.1038/sj.emboj.7600789
Source: PubMed


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.

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Available from: Julien Sage, Oct 06, 2015
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    • "In contrast, control shRNAmir expressing cells transduced with KRasV12 cDNA failed to increase in number, did not form colonies when plated at low densities and had a much reduced BrdU incorporation rate (11%). These data are consistent with those observed by others, that oncogenic Ras induces growth arrest in primary cells [6], [29], [60], [62], [63]. Transduction with shRNAmirs targeting p53 lead to increased proliferation and efficient colony formation for both mCherry and KRasV12 expressing cells. "
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    PLoS ONE 10/2013; 8(10):e76279. DOI:10.1371/journal.pone.0076279 · 3.23 Impact Factor
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    • "As a human disease, PHPV is typically sporadic, but several reports of familial disease suggest that it could have an underlying genetic basis [48], [49], [50]. C/ebpβ is frequently expressed in human cancer and has been implicated as an oncogenic factor (as in the keratinocyte model noted above) [26], [40] or tumor suppressor with the capacity to foster senescence [51], [52]. These disparate effects may be due, in part, to the capacity of C/ebpβ to form homo- and heterodimeric complexes with either activating or transcriptional repressive activity [28]. "
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    • "C/EBPbeta is required for oncogene-induced senescence, both by oncogenic Ras and activated Raf [20], [21]. We recently demonstrated that C/EBPbeta1 is the primary transactivator isoform responsible for the induction of senescence [14]. "
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