The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs.
This report examines the cytotoxicity of chemotherapeutic agents to primary bone marrow-derived IL-3-dependent cells. Such cells derived from p53-null mice were resistant to almost 100-fold higher concentrations of the inhibitors of deoxyribonucleotide synthesis FUdR, methotrexate and hydroxyurea than cells with wild-type p53. In contrast, the cytotoxicity of the DNA damaging agents X-irradiation, cisplatin or bleomycin was p53-independent. The topoisomerase II inhibitor etoposide induced p53-dependent death, which suggests that DNA damage may not be its primary mechanism of cytotoxicity in this cell type. An IL-3-dependent cell line which expresses wild-type p53 was used to demonstrate that the ability of cytotoxic drugs to increase p53 expression level does not control their ability to induce p53-dependent loss of clonigenicity. Finally, comparison with a p53-null IL-3-dependent cell line was used to show that absence of p53 delays the rate of entry into apoptosis following treatment with either DNA damaging agents or inhibitors of deoxyribonucleotide synthesis. This distinguishes short-term effects of p53 on rate of entry into apoptosis from its role in controlling ultimate cell survival. Oncogene (2000) 19, 3556 - 3559
Department of Immunology, Windeyer Institute of Medical Science, 46 Cleveland Street, London W1P 6DB, UK.
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Palacios
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Gutierrez del Arroyo
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Silva
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Collins
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D001761:Bleomycin / Q000633:toxicity; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005047:Etoposide / Q000633:toxicity; D005467:Floxuridine / Q000633:toxicity; D016158:Genes, p53; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D006918:Hydroxyurea / Q000633:toxicity; D007377:Interleukin-3 / Q000494:pharmacology*; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011836:Radiation Tolerance / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D016159:Tumor Suppressor Protein p53; D005467:Floxuridine; D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin; D006918:Hydroxyurea; D008727:Methotrexate