A new look at the role of p53 in leukemia cell sensitivity to chemotherapy
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A new look at the role of p53 in leukemia cell sensitivity to chemotherapy. / Trepel, M; Scheding, S; Groscurth, P; Horny, H P; Malipiero, U; Brugger, Wolfram; Dichgans, Johannes; Weller, M.
in: LEUKEMIA, Jahrgang 11, Nr. 11, 11.1997, S. 1842-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -