Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity.
Loss of p53 function has been shown to cause increased resistance to ionizing radiation in normal murine cells; however, the role of p53 in radioresistance of human tumor cells is less clear. Since wild-type p53 function is required for radiation-induced G1 arrest, we measured G1 arrest in 12 human tumor cell lines that have a wide range of radiosensitivities (surviving fraction at 2 Gy, 0.11-0.8). We observed a significant correlation between the level of ionizing radiation-induced G1 arrest and radiosensitivity. Cell lines having G1 arrest are more radiosensitive. There is no correlation between maximal G2 arrest and radiosensitivity. Expression of a dominant-negative mutant of p53 (codon 143, Val to Ala) in transfectants of the radiosensitive human ovarian cell line A2780 abrogates the radiation-induced G1 arrest. Such mutant p53 transfectants are more resistant to ionizing radiation than the parental line and vector-alone transfectants, as measured by clonogenic assays. These results support the concept that wild-type p53 function is required for sensitivity of tumor cells to DNA-damaging agents, such as ionizing radiation, and that the loss of p53 function in certain human tumor cells can lead to resistance to ionizing radiation.
McIlwrath
A J
AJ
CRC Department of Medical Oncology, CRC Beatson Laboratories, Bearsden Glasgow, United Kingdom.
Vasey
P A
PA
Ross
G M
GM
Brown
R
R
D016193:G1 Phase / Q000528:radiation effects*; D016195:G2 Phase / Q000528:radiation effects; D006801:Humans; D011836:Radiation Tolerance; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53