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

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 onco genic functions. To distinguish between the dominant-negative effect and gain of new function of p53 missense mutants, we measured the abifity of transfected missense mutant pS3s 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@, @ser and 273@) enhanced the frequency of TCR mutants after graded doses of X-radiation compared to null p53 parentand wild-type p53possessing normal lymphocytes; the parent Jurkat and normal lympho. cyte 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 kineticsor cell death,may be responsiblefor the selectionof certain p53 point mutations, which eventually result in the twnorigenesis of the cell.