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Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta
Thomas Sebastian1, Peter F Johnson
1Laboratory of Protein Dynamics and Signaling, NCI-Frederick, Frederick, Maryland 21702-1201, USA.
Abstract:
Oncogene-induced senescence (OIS) is an irreversible form of cell cycle arrest that can be elicited by overexpression of oncogenes such as RasV12 and requires activation of the Arf-p53 and RB tumor suppressor pathways. Increasing evidence implicates senescence as a bona fide tumor suppression mechanism in vivo. We recently discovered that the bZIP transcription factor C/EBPbeta, a downstream target of Ras signaling, is an essential component of RasV12-mediated senescence in mouse embryo fibroblasts (MEFs). C/EBPbeta induces cell cycle arrest through a mechanism requiring RB:E2F repressor complexes and negatively regulates several E2F target genes. Although C/EBPbeta has tumor suppressor-like activity in MEFs, other observations point to critical pro-oncogenic functions for C/EBPbeta in certain cancers. Here we review the evidence for positive and negative cell cycle regulation by C/EBPbeta and discuss possible mechanisms by which this transcription factor could participate in both cellular senescence and oncogenic transformation.
Insights
Oncogene-induced senescence (OIS) involves cell cycle arrest and tumor suppression. The transcription factor C/EBPbeta is crucial for RasV12-induced senescence, acting as a tumor suppressor in mouse cells, but may promote cancer in others.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Oncogene-induced senescence (OIS) is a cell cycle arrest mechanism activated by oncogene expression.
- OIS functions as a tumor suppression pathway, involving key regulators like Arf-p53 and RB.
- The transcription factor C/EBPbeta is a downstream target of Ras signaling.
Purpose of the Study:
- To review the dual role of C/EBPbeta in cell cycle regulation.
- To discuss C/EBPbeta's function in both senescence and oncogenic transformation.
- To highlight C/EBPbeta as an essential component in RasV12-mediated senescence.
Main Methods:
- Review of existing scientific literature on C/EBPbeta and senescence.
- Analysis of C/EBPbeta's role in RasV12-induced senescence in mouse embryo fibroblasts (MEFs).
- Investigation of C/EBPbeta's regulation of E2F target genes via RB:E2F complexes.
Main Results:
- C/EBPbeta is essential for RasV12-mediated senescence in MEFs.
- C/EBPbeta induces cell cycle arrest by negatively regulating E2F target genes.
- Evidence suggests C/EBPbeta exhibits tumor suppressor-like activity in MEFs.
Conclusions:
- C/EBPbeta plays a critical role in initiating oncogene-induced senescence.
- C/EBPbeta's function is context-dependent, showing both tumor suppressive and oncogenic roles.
- Understanding C/EBPbeta's mechanisms is key to deciphering its role in cancer development.
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