Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines.
We have assessed the role of the p53 tumor suppressor gene in cell cycle arrest and cytotoxicity of ionizing radiation in 17 Burkitt's lymphoma and lymphoblastoid cell lines. Cell cycle arrest was assessed by flow cytometry of cells 16 h following irradiation. In addition to the usual G2 arrest, the cell lines exhibited three types of responses in G1: Class I, strong arrest in G1 following radiation; Class II, minimal arrest; and Class III, an intermediate response. All Class I cells contained normal p53 genes. Of the ten lines that showed minimal G1 arrest, eight had mutant p53 alleles, and two lines were heterozygous for p53 mutations. Both of the lines showing an intermediate response contained wild-type p53. Our results are consistent with the view that mutations abrogate the ability of p53 to induce G1 arrest following radiation. Studies with the heterozygotes showed that the mutant protein can have a dominant negative influence upon wild-type p53, and the reduced ability of two normal p53 lines to arrest in G1 indicated that p53 function can be impaired by other mechanisms. The radiosensitivity of most of the lines appeared to depend on the ability of p53 to induce a G1 arrest. The mean radiation dose that inhibited proliferation of the Class I lines by 50% was 0.98 Gy. Of the eight p53 mutant cell lines tested, five lines required approximately 2.9 Gy to cause a 50% inhibition of cell proliferation. The two heterozygotes were also more resistant to radiation than the Class I cells (50% inhibitory dose, 2.1 and 2.9 Gy). Our results suggest that radioresistance is afforded by a loss of function of wild-type p53, which would normally induce a G1 arrest and promote cell death in the presence of DNA damage.
O'Connor
P M
PM
Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Jackman
J
J
Jondle
D
D
Bhatia
K
K
Magrath
I
I
Kohn
K W
KW
D002051:Burkitt Lymphoma / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects*; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D016193:G1 Phase / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays; D016158:Genes, p53; D006801:Humans; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
D016159:Tumor Suppressor Protein p53