ROLE OF THE P53 TUMOR-SUPPRESSOR GENE IN CELL-CYCLE ARREST AND RADIOSENSITIVITY OF BURKITTS-LYMPHOMA CELL-LINES

We have assessed the role of the p53 tumor suppressor gene in cell cyc le arrest and cytotoxicity of ionizing radiation in 17 Burkitt's lymph oma and lymphoblastoid cell lines. Cell cycle arrest was assessed by f low 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, minima l arrest; and Class III, an intermediate response. All Class I cells c ontained normal p53 genes. Of the ten lines that showed minimal G1 arr est, eight had mutant p53 alleles, and two lines were heterozygous for p53 mutations. Both of the lines showing an intermediate response con tained wild-type p53. Our results are consistent with the view that mu tations abrogate the ability of p53 to induce G1 arrest following radi ation. Studies with the heterozygotes showed that the mutant protein c an have a dominant negative influence upon wild-type p53, and the redu ced 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 t he Class I lines by 50% was 0.98 Gy. Of the eight p53 mutant cell line s tested, five lines required approximately 2.9 Gy to cause a 50% inhi bition of cell proliferation. The two heterozygotes were also more res istant to radiation than the Class I cells (50% inhibitory dose, 2.1 a nd 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 ar rest and promote cell death in the presence of DNA damage.