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p53 protein accumulation in addition to the transactivation activity is required for p53-dependent cell cycle arrest after treatment of cells with camptothecin

Oncogene volume 20, pages 1212–1219 (2001)Cite this article

Abstract

In this study we characterize the connections between p53-dependent G1 cell cycle arrest, transcriptional activation of the protein and the increase of its intracellular steady-state concentration. Several cell lines expressing wild-type p53 protein were treated with increasing concentrations of DNA-damaging drug camptothecin. Lower doses of the drug caused transcriptional activation of p53, but no accumulation of the protein was detected. Only after a certain threshold dose of camptothecin does the amount of the protein rapidly increase and reach its plateau levels. The threshold dose was different for different cell lines, but the general non-linear profile was similar. Increase of p53 level was accompanied by additional transcriptional activation of some p53 target genes (i.e. waf1), but not the others (mdm2). We demonstrate here that transcriptional activation of p53 after the treatment of camptothecin is not sufficient to cause p53-dependent G1 cell cycle arrest. The latter is observable only after the inrease of steady-state level of p53. Low drug concentrations, although accompanied by transcriptional activation of p53, do not cause either p53 protein accumulation nor cell cycle arrest at G1. We propose a model for p53 acting as a part of cellular sensor system detecting the severity of DNA damage.

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Acknowledgements

We thank Dr Arnold Levine, Princeton University, for 10(1) cell line, Dr Marikki Laiho for critically reviewing the manuscript; Drs Jane Lehtmaa and Ain Kaare, Clinic of Hematology and Oncology, Tartu University for opportunity to use flow cytometer and for personal help. This work has been partly supported by contract QLG7-CT-1999-00851 from the European Community and grant no.4029 from Estonian Science Foundation.

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  1. Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Riia23, Tartu, 51010, Estonia

    Viljar Jaks, Arvi Jõers, Arnold Kristjuhan & Toivo Maimets

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Jaks, V., Jõers, A., Kristjuhan, A. et al. p53 protein accumulation in addition to the transactivation activity is required for p53-dependent cell cycle arrest after treatment of cells with camptothecin. Oncogene 20, 1212–1219 (2001). https://doi.org/10.1038/sj.onc.1204232

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