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  • Original Paper
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Attenuation of the p53 response to DNA damage by high cell density

Oncogene volume 23, pages 2128–2137 (2004)Cite this article

Abstract

The p53 tumor suppressor is critical for preventing cancer progression. Numerous observations suggest that p53 function can be modulated by the cells' microenvironment. We addressed specifically the impact of cell crowding on the induction of p53 by DNA damage. We report that cell crowding attenuates markedly p53 upregulation, transcriptional activation and subsequent p53-dependent apoptosis following exposure to genotoxic stress. The p53 protein remains short-lived in confluent cultures regardless of the extent of DNA damage, even though it undergoes efficient phosphorylation on the mouse equivalent of human p53 serine 15. This inhibitory effect of cell crowding is not a secondary consequence of density-dependent cell cycle arrest (contact inhibition). Microscopic examination indicates that dense cultures display prominent cadherin-mediated cell–cell junctions, and only poor cell–matrix focal adhesions, whereas sparse cells possess conspicuous matrix adhesions and essentially no cell–cell contacts. High-density cell culture might recapitulate the microenvironment of cells in a living organism, where the response of p53 to DNA damage is reported to be low in some organs and ages. The impact of cell density on p53 activation may have important bearings on the involvement of p53 in tumor suppression and the cellular response to anticancer therapy.

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Acknowledgements

We thank Drs M Roussel and CJ Sherr for the gift of ARF-null MEFs, Dr D Lane for p53-specific antibodies, Dr Y Taya for antiphosphoserine 15 antibodies and Dr G Nolan for the LZRSpBMN-IRES-EGFP plasmid. BG holds the E Neter chair in cell and tumor biology. This work was supported in part by Grant RO1 CA 40099 from the National Cancer Institute (USA), The USA–Israel Binational Science Foundation, the German–Israel Project Cooperation (DIP), the Kadoorie Charitable Foundations, the Center for Excellence Program of the Israel Science Foundation and the Yad Abraham Center for Cancer Diagnosis and Therapy.

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  1. Department of Molecular Cell Biology, Weizmann Institute of Science, POB26, Rehovot, 76100, Israel

    Jair Bar, Efrat Cohen-Noyman, Benjamin Geiger & Moshe Oren

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Correspondence to Moshe Oren.

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Bar, J., Cohen-Noyman, E., Geiger, B. et al. Attenuation of the p53 response to DNA damage by high cell density. Oncogene 23, 2128–2137 (2004). https://doi.org/10.1038/sj.onc.1207325

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