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E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest
Benjamin D Rowland1, Serguei G Denissov, Sirith Douma
1Division of Molecular Carcinogenesis, Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Abstract:
The p16(INK4a)/pRB/E2F and p19(ARF)/p53 tumor suppressor pathways are disrupted in most human cancers. Both p19(ARF) and p53 are required for the induction of senescence in primary mouse embryonic fibroblasts (MEFs), but little is known about their downstream targets. Disruption of E2F-mediated transcriptional repression in MEFs caused a general increase in the expression of E2F target genes, including p19ARF. We detected no contribution of E2F-mediated transactivation in this setting, indicating that a predominant role of endogenous E2F in asynchronously growing primary MEFs is to repress its target genes. Moreover, relief of transcriptional repression by E2F rendered MEFs resistant to senescence induced by either p19(ARF), p53, or RAS(V12). Thus, E2F transcriptional repressor complexes are critical downstream targets of antiproliferative p19(ARF)/p53 signaling.
Insights
E2F repressor complexes are key downstream targets of tumor suppressor pathways like p19ARF/p53. Inhibiting E2F repression prevents senescence, highlighting its role in cancer development.
Area of Science:
- Molecular biology
- Cellular senescence
- Cancer research
Background:
- The p16(INK4a)/pRB/E2F and p19(ARF)/p53 pathways are crucial tumor suppressors frequently disrupted in human cancers.
- While p19(ARF) and p53 are known to induce senescence in mouse embryonic fibroblasts (MEFs), their downstream targets remain largely uncharacterized.
Purpose of the Study:
- To investigate the role of E2F transcriptional repression in regulating senescence.
- To identify downstream targets of the p19(ARF)/p53 signaling pathway.
Main Methods:
- Studied disruption of E2F-mediated transcriptional repression in primary MEFs.
- Analyzed the expression of E2F target genes, including p19ARF.
- Assessed the impact of E2F repression relief on senescence induction by p19(ARF), p53, or RAS(V12).
Main Results:
- Disruption of E2F repression led to increased expression of E2F target genes, notably p19ARF.
- Endogenous E2F primarily functions to repress target genes in asynchronously growing MEFs.
- Relief of E2F-mediated repression conferred resistance to senescence induced by p19(ARF), p53, or RAS(V12).
Conclusions:
- E2F transcriptional repressor complexes are critical downstream targets of the antiproliferative p19(ARF)/p53 signaling pathway.
- E2F-mediated repression plays a vital role in the induction of cellular senescence.