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Role of the p53 Tumor Suppressor Gene in Cell Cycle Arrest and Radiosensitivity of Burkitt's Lymphoma Cell Lines

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment [P. M. O., J. J., D. J., K. W. K.], and Lymphoid Biology Section, Pediatrics Branch [K. B., I. M.], National Cancer Institute, NIH, Bethesda, Maryland 20892

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 1, 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.

¹ To whom requests for reprints should be addressed, at Room 5C-25, Bldg. 37, National Cancer Institute, Bethesda, MD 20892.

Received 8/13/93. Accepted 9/ 2/93.

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