A NEW LOOK AT THE ROLE OF P53 IN LEUKEMIA-CELL SENSITIVITY TO CHEMOTHERAPY

A gene encoding the p53 val(135) mutant, which assumes mutant conforma tion at 38.5 degrees C and wild-type conformation at 32.5 degrees C, w as introduced into p53-deficient K562 myeloid leukemia cells. Forced e xpression of wild-type, but not mutant, p53 resulted in growth arrest, accumulation of p21 and Fax proteins, and delayed cell death. Wild-ty pe p53 enhanced the cytotoxic effects of some drugs and attenuated tho se of others. Compared with wild-type p53, mutant p53 induced much str onger sensitization to drug cytotoxicity. This occurred in the absence of effects on cell cycle progression or activation of several p53 tar get genes. Although both mutant and wild-type p53 induced changes of i mmunophenotype, no specific pattern of differentiation was associated with enhanced chemosensitivity. Thus, (1) induction of growth arrest a nd activation of p53 target genes such as p21 and bar are linked to th e wild-type conformation of p53; (2) p53 induces immunophenotypic chan ges of myeloid leukemia cells suggestive of multidirectional different iation in a conformation-dependent manner; and (3) (so-called) mutant p53 induces chemosensitization in the absence of effects on cell cycle progression, activation of bar, p21, gadd45 and mdm-2, or a specific pattern of differentiation; and (4) chemosensitization mediated by wil d-type p53 may be masked by transcription-dependent induction of growt h arrest.