C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence
Thomas Sebastian1, Radek Malik, Sara Thomas
1Laboratory of Protein Dynamics and Signaling, NCI-Frederick, Frederick, MD 21702-1201, USA.
The EMBO Journal
|August 19, 2005
Summary
The transcription factor C/EBPbeta is essential for oncogene-induced senescence, a cell cycle arrest that prevents tumor formation. This protein acts independently of p53 and pRB pathways to suppress cell proliferation.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Oncogene activation in primary cells can trigger premature senescence, an irreversible cell cycle arrest.
- Senescence, regulated by pathways like p19ARF/p53 and p16INK4a/pRB, acts as a tumor suppressor mechanism.
- The precise molecular components initiating and executing oncogene-induced senescence remain under investigation.
Purpose of the Study:
- To investigate the role of the transcription factor C/EBPbeta in oncogene-induced senescence.
- To determine the relationship between C/EBPbeta and the known senescence pathways (p19ARF/p53 and p16INK4a/pRB).
- To elucidate the mechanism by which C/EBPbeta influences cell proliferation and senescence.
Main Methods:
- Utilized mouse embryo fibroblasts (MEFs) lacking C/EBPbeta (C/EBPbeta-/-) and wild-type MEFs.
- Overexpressed oncogenic Ras (Ras(V12)) in MEFs to induce senescence.
- Assessed cell proliferation, senescence markers, and expression of cell cycle regulators.
- Performed chromatin immunoprecipitation (ChIP) assays to examine C/EBPbeta binding to gene promoters.
Main Results:
- Ras(V12)-induced senescence was impaired in C/EBPbeta-/- MEFs, which continued to proliferate.
- C/EBPbeta expression inhibited proliferation in wild-type MEFs and slowed it in p19Arf-/- and p53-/- cells.
- C/EBPbeta failed to inhibit proliferation in cells lacking RB family proteins or expressing dominant-negative E2F-1; instead, it promoted growth.
- C/EBPbeta repressed the expression of E2F target genes, indicating a role in cell cycle control.
Conclusions:
- C/EBPbeta is a critical transcription factor required for Ras(V12)-induced senescence.
- C/EBPbeta functions downstream or independently of the p19ARF/p53 pathway in senescence.
- C/EBPbeta's mechanism involves repressing E2F target genes essential for cell cycle progression.
- C/EBPbeta is a novel component of the RB:E2F-dependent senescence program activated by oncogenic stress.
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