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Gain-of-Function p53 Mutations Enhance Alteration of the T-Cell Receptor following X-Irradiation, Independently of the Cell Cycle and Cell Survival¹

Department of Radiobiology, Radiation Effects Research Foundation, Hiroshima 732, Japan

Missense mutations are by the far the most common types of mutations found in p53 of human tumors, suggesting that mutant p53 proteins function either by abrogating wild-type function or by gaining new oncogenic functions. To distinguish between the dominant-negative effect and gain of new function of p53 missense mutants, we measured the ability of transfected missense mutant p53s in p53-null Jurkat cells to alter T-cell receptor (TCR) surface expression. The TCR is a key signal transduction moiety common to T lymphocytes and is one of the major sites for aberrations in T-cell leukemias/lymphomas. Three p53 mutants (248^trp, 249^ser, and 273^his) enhanced the frequency of TCR mutants after graded doses of X-radiation compared to null p53 parent- and wild-type p53-possessing normal lymphocytes; the parent Jurkat and normal lymphocyte showed no difference. These enhancements were not the results of a change in radiosensitivity or in G₁ checkpoint arrest characteristics. Therefore, the creation of this mutator phenotype by missense-type p53 mutations implies that a more direct mechanism, apart from changes of cell cycle kinetics or cell death, may be responsible for the selection of certain p53 point mutations, which eventually result in the tumorigenesis of the cell.

¹ This publication is based on research performed at the Radiation Effects Research Foundation, Hiroshima, Japan. The Radiation Effects Research Foundation is a private nonprofit foundation funded equally by the Japanese Ministry of Health and Welfare and the United States Department of Energy through the National Academy of Sciences.

² To whom requests for reprints should be addressed, at Department of Radiobiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minani-Ku, Hiroshima 732, Japan.

Received 5/31/96. Accepted 7/16/96.

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