Reversal of p53-induced cell-cycle arrest.
Activation of the tumor suppressor protein p53 can lead to arrest in both G1 and G2 stages of the cell cycle and, in some cells, to apoptotic cell death. In this study, we showed that the p53 response to a chemotherapeutic drug, actinomycin D, was reversible in both normal and tumor cells, even when a substantial proportion of tumor cells were undergoing apoptosis. Despite the clear reversibility of the p53-induced cell-cycle arrest after removal of actinomycin D, a substantial proportion of the cells arrested in G2 failed to resume normal cell-cycle progression and underwent another round of DNA synthesis. This endoreduplication probably reflects a function of the cyclin-dependent kinase inhibitor p21Waf1Cip1, which is expressed in response to p53. Our observation that this abnormal re-replication of DNA occurred in both transformed and untransformed cells after reversal of a p53 response may have implications for the eventual outcome of tumor therapies in which p53 is transiently expressed in a substantial number of normal as well as tumor cells.
Bates
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ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Hickman
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Vousden
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D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D016193:G1 Phase; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D016296:Mutagenesis; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin