A new look at the role of p53 in leukemia cell sensitivity to chemotherapy

TY - JOUR

T1 - A new look at the role of p53 in leukemia cell sensitivity to chemotherapy

AU - Trepel, M

AU - Scheding, S

AU - Groscurth, P

AU - Horny, H P

AU - Malipiero, U

AU - Brugger, Wolfram

AU - Dichgans, Johannes

AU - Weller, M

PY - 1997/11

Y1 - 1997/11

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Cell Cycle

KW - Cell Division

KW - Drug Resistance, Neoplasm

KW - Flow Cytometry

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunohistochemistry

KW - Leukemia, Myeloid

KW - Mice

KW - Microscopy, Electron

KW - Mutation

KW - Temperature

KW - Transfection

KW - Tumor Cells, Cultured

KW - Tumor Suppressor Protein p53

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - SCORING: Journal article

C2 - 9369416

VL - 11

SP - 1842

EP - 1849

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 11

ER -