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Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21(CIP1)-dependent senescence.
- Source :
-
Oncogene [Oncogene] 2010 Oct 14; Vol. 29 (41), pp. 5579-90. Date of Electronic Publication: 2010 Aug 02. - Publication Year :
- 2010
-
Abstract
- E2F1-3 proteins appear to have distinct roles in progenitor cells and in differentiating cells undergoing cell cycle exit. However, the function of these proteins in paradigms of terminal differentiation that involve continued cell division has not been examined. Using compound E2F1/E2F2-deficient mice, we have examined the effects of E2F1 and E2F2 loss on the differentiation and simultaneous proliferation of bone-marrow-derived cells toward the macrophage lineage. We show that E2F1/E2F2 deficiency results in accelerated DNA replication and cellular division during the initial cell division cycles of bone-marrow-derived cells, arguing that E2F1/E2F2 are required to restrain proliferation of pro-monocyte progenitors during their differentiation into macrophages, without promoting their cell cycle exit. Accelerated proliferation is accompanied by early expression of DNA replication and cell cycle regulators. Remarkably, rapid proliferation of E2F1/E2F2 compound mutant cultures is temporally followed by induction of a DNA damage response and the implementation of a p21(CIP1)-dependent senescence. We further show that differentiating E2F1/E2F2-knockout macrophages do not trigger a DNA damage response pathway in the absence of DNA replication. These findings underscore the relevance of E2F1 and E2F2 as suppressors of hematopoietic progenitor expansion. Our data indicate that their absence in differentiating macrophages initiates a senescence program that results from enforcement of a DNA damage response triggered by DNA hyper-replication.
- Subjects :
- Animals
Bone Marrow Cells cytology
Bone Marrow Cells metabolism
Cell Cycle
Cell Differentiation
Cell Proliferation
Cells, Cultured
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p21 genetics
E2F1 Transcription Factor genetics
E2F2 Transcription Factor genetics
Flow Cytometry
Immunoblotting
Macrophages cytology
Mice
Mice, Knockout
Time Factors
Cyclin-Dependent Kinase Inhibitor p21 metabolism
DNA Damage
DNA Replication
E2F1 Transcription Factor metabolism
E2F2 Transcription Factor metabolism
Macrophages metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 29
- Issue :
- 41
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 20676136
- Full Text :
- https://doi.org/10.1038/onc.2010.296