Oncogene, 2006-06, Vol.25 (23), p.3258-3266
2006
Details
- Autor(en) / Beteiligte
- Titel
- E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts
- Ist Teil von
- Oncogene, 2006-06, Vol.25 (23), p.3258-3266
- Ort / Verlag
- Basingstoke: Nature Publishing
- Erscheinungsjahr
- 2006
- Link zum Volltext
- Quelle
- Alma/SFX Local Collection
- Beschreibungen/Notizen
- Deregulation of the Rb/E2F pathway in human fibroblasts results in an E2F1-mediated apoptosis dependent on Atm, Nbs1, Chk2 and p53. Here, we show that E2F1 expression results in MRN foci formation, which is independent of the Nbs1 interacting region and the DNA-binding domain of E2F1. E2F1-induced MRN foci are similar to irradiation-induced foci (IRIF) that result from double-strand DNA breaks because they correlate with 53BP1 and gammaH2AX foci, do not form in NBS cells, do form in AT cells and do not correlate with cell cycle entry. In fact, we find that in human fibroblasts deregulated E2F1 causes a G1 arrest, blocking serum-induced cell cycle progression, in part through an Nbs1/53BP1/p53/p21(WAF1/CIP1) checkpoint pathway. This checkpoint protects against apoptosis because depletion of 53BP1 or p21(WAF1/CIP1) increases both the rate and extent of apoptosis. Nbs1 and p53 contribute to both checkpoint and apoptosis pathways. These results suggest that E2F1-induced foci generate a cell cycle checkpoint that, with sustained E2F1 activity, eventually yields to apoptosis. Uncontrolled proliferation due to Rb/E2F deregulation as well as inactivation of both checkpoint and apoptosis programs would then be required for transformation of normal cells to tumor cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/sj.onc.1209352Titel-ID: cdi_proquest_miscellaneous_68031054
- Format
- –
- Schlagworte
- Acid Anhydride Hydrolases, Ageing, cell death, Apoptosis, Apoptosis - physiology, Biological and medical sciences, Cell cycle, Cell Cycle - physiology, Cell Cycle Proteins - physiology, Cell cycle, cell proliferation, Cell Line, Cell physiology, Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes, CHK2 protein, Cyclin-dependent kinase inhibitor p21, Cyclin-Dependent Kinase Inhibitor p21 - physiology, Deoxyribonucleic acid, Deregulation, DNA, DNA damage, DNA Damage - physiology, DNA Repair - physiology, DNA Repair Enzymes - metabolism, DNA-Binding Proteins - metabolism, E2F1 protein, E2F1 Transcription Factor - metabolism, E2F1 Transcription Factor - physiology, Fibroblasts, Fibroblasts - cytology, Fibroblasts - metabolism, Fundamental and applied biological sciences. Psychology, Gene expression, Humans, Intracellular Signaling Peptides and Proteins - physiology, Molecular and cellular biology, MRE11 Homologue Protein, Nuclear Proteins - physiology, Oncology, p53 Protein, Phosphoproteins - physiology, Radiation, Signal transduction, Tumor cells, Tumor Suppressor p53-Binding Protein 1, Tumor Suppressor Protein p53 - physiology