A new look at the role of p53 in leukemia cell sensitivity to chemotherapy.
A gene encoding the p53 val135 mutant, which assumes mutant conformation at 38.5 degrees C and wild-type conformation at 32.5 degrees C, was introduced into p53-deficient K562 myeloid leukemia cells. Forced expression of wild-type, but not mutant, p53 resulted in growth arrest, accumulation of p21 and Bax proteins, and delayed cell death. Wild-type p53 enhanced the cytotoxic effects of some drugs and attenuated those of others. Compared with wild-type p53, mutant p53 induced much stronger sensitization to drug cytotoxicity. This occurred in the absence of effects on cell cycle progression or activation of several p53 target genes. Although both mutant and wild-type p53 induced changes of immunophenotype, no specific pattern of differentiation was associated with enhanced chemosensitivity. Thus, (1) induction of growth arrest and activation of p53 target genes such as p21 and bax are linked to the wild-type conformation of p53; (2) p53 induces immunophenotypic changes of myeloid leukemia cells suggestive of multidirectional differentiation in a conformation-dependent manner; and (3) (so-called) mutant p53 induces chemosensitization in the absence of effects on cell cycle progression, activation of bax, p21, gadd45 and mdm-2, or a specific pattern of differentiation; and (4) chemosensitization mediated by wild-type p53 may be masked by transcription-dependent induction of growth arrest.
Trepel
M
M
Department of Neurology, University of Tübingen, Medical School, Germany.
Scheding
S
S
Groscurth
P
P
Horny
H P
HP
Malipiero
U
U
Brugger
W
W
Dichgans
J
J
Weller
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008854:Microscopy, Electron; D009154:Mutation; D013696:Temperature; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53