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  • Original Paper
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Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

Oncogene volume 22, pages 1668–1677 (2003)Cite this article

Abstract

p53 and DNA methylation play key roles in the maintenance of genome stability. In this work, we demonstrate that the two mechanisms are linked and that p53 plays a role in the maintenance of the DNA methylation levels. The loss of p53 was shown to induce loss of DNA methylation in the TROP1 gene, a human cancer-expressed locus that undergoes amplification when hypomethylated. This demethylation was reverted by the reintroduction of a wild-type TP53 (wtTP53) in the TP53-null cells. Using a gene-amplification assay in vivo, we demonstrate that the loss of p53 leads to a demethylation-dependent TROP1 gene amplification. The induction of gene amplification was reverted by the expression of a wtTP53 gene or by in vitro methylation of the transfected DNA with the Sss I DNA methylase. Taken together, these findings demonstrate that the inactivation of TP53 induces loss of DNA methylation and DNA methylation-dependent gene amplification.

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Acknowledgements

We thank Dr M Tainsky for kindly supplying the Li–Fraumeni cells and Drs A Sacchi and E Giulotto for useful discussions. We gratefully acknowledge the support of the Italian Association for Cancer Research (AIRC).

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Author notes

  1. Michele Nutini & Emanuela Guerra

    Present address: Institute of Medicine and Aging, University G. D'Annunzio Medical School, Chieti, Italy

Authors and Affiliations

  1. Department of Cell Biology and Oncology, Laboratory of Experimental Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri,’-Consorzio Mario Negri Sud, via Nazionale, Santa Maria Imbaro (Chieti), 66030, Italy

    Ashraf F Nasr, Michele Nutini, Barbara Palombo, Emanuela Guerra & Savenio Alberti

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  1. Ashraf F Nasr
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  2. Michele Nutini
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Correspondence to Savenio Alberti.

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Nasr, A., Nutini, M., Palombo, B. et al. Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene. Oncogene 22, 1668–1677 (2003). https://doi.org/10.1038/sj.onc.1206248

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