Cell cycle synchrony unmasks the influence of p53 function on radiosensitivity of human glioblastoma cells.
Although ionizing radiation causes DNA damage that can play a role in tumorigenesis, such irradiation is also an important modality of cancer therapy. We studied the radiation response of the U-87 MG human glioblastoma cell line and transfected derivatives in which p53 function had been inactivated. Although little effect of p53 on the radiation sensitivity of asynchronously growing cultures could be detected, inactivation of p53 resulted in a large increase in clonogenic survival when cells synchronized by mitotic selection were irradiated in early G1. The radiation dose sufficient to reduce cellular clonogenicity by 1 log in cells expressing functional p53 was 3.26 +/- 0.12 Gy, whereas a much higher dose (7.41 +/- 0.44 Gy) was required to achieve the same killing effect in cells in which p53 was inactivated. Apoptosis was excluded as a probable mechanism contributing to the radiosensitivity of these cells. Fluorescence-activated cell sorter analysis, continuous labeling with tritiated thymidine, and time-lapse videomicroscopy documented the first example of a prolonged p53-dependent G1 arrest induced by ionizing radiation during the first postirradiation cell cycle of tumor cells, suggesting a role for G1 arrest in determining the sensitivity of these cells to irradiation.
Yount
G L
GL
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143, USA.
Haas-Kogan
D A
DA
Vidair
C A
CA
Haas
M
M
Dewey
W C
WC
Israel
M A
MA
D002453:Cell Cycle / Q000502:physiology; D016193:G1 Phase / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D009154:Mutation; D011836:Radiation Tolerance / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53