E2F-1 has properties of a radiosensitizer and its regulation by cyclin A kinase is required for cell survival of fibrosarcoma cells lacking p53.
Negative regulation of E2F-1 DNA binding function by cyclin A kinase represents part of an S-phase checkpoint control system that, when activated, leads to apoptosis. In this study, we examined the cellular sensitivity and resistance of isogenic mouse fibrosarcoma cell lines, differing primarily in their p53 status, to ectopic expression of wild-type (wt) E2F-1 and cyclin A kinase binding-defective mutants of it. We found that E2F-1 (wt) potently affected the survival of p53+/+ tumor cells but not that of p53-/- cells. In contrast, expression of cyclin A kinase binding-defective E2F-1 species interfered with cell survival of fibrosarcoma cells irrespective of their p53 status. Finally, expression of E2F-1 (wt) in p53-/- fibrosarcoma cells enhanced the cytotoxic effect of ionizing radiation in vitro and in vivo in a mouse tumor model. These results suggest that E2F-1-dependent activation of an S-phase checkpoint is p53 independent and that E2F-1 possesses radiosensitizing properties in the absence of p53.
Pruschy
M
M
Department of Radiation Oncology, University Hospital Zürich, Switzerland.
Wirbelauer
C
C
Glanzmann
C
C
Bodis
S
S
Krek
W
W
D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002470:Cell Survival; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016158:Genes, p53; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D011691:Puromycin / Q000378:metabolism; D011836:Radiation Tolerance / Q000502:physiology; D056465:Retinoblastoma-Binding Protein 1; D013997:Time Factors; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011500:Protein Synthesis Inhibitors; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D011691:Puromycin; D011494:Protein Kinases; C102333:histone H1 kinase