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  • Original Paper
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C-myc overexpression and p53 loss cooperate to promote genomic instability

Oncogene volume 18, pages 1177–1184 (1999)Cite this article

Abstract

p53 monitors genomic integrity at the G1 and G2/M cell cycle checkpoints. Cells lacking p53 may show gene amplification as well as the polyploidy or aneuploidy typical of many tumors. The pathways through which this develops, however, are not well defined. We demonstrate here that the combination of p53 inactivation and c-myc overexpression in diploid cells markedly accelerates the spontaneous development of tetraploidy. This is not seen with either N-myc or L-myc. Tetraploidy is accompanied by significantly higher levels of cyclin B and its associated cdc2 kinase activity. Mitotic spindle poisons accelerate the appearance of tetraploidy in cells either lacking functional p53 or overexpressing c-myc whereas the combination is additive. Restoration of p53 function in cells overexpressing c-myc causing rapid apoptosis, indicating that cells yet to become tetraploid have nonetheless suffered irreversible genomic and/or mitotic spindle damage. In the face of normal p53 function, such damage would either be repaired or trigger apoptotis. We propose that loss of p53 and overexpression of c-myc permits the emergence and survival of cells with increasingly severe damage and the eventual development of tetraploidy.

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Acknowledgements

We thank Saijun Fan, and Karen Vousden for gifts of wild-type and mutant E6 genes, Mike Clarke for pLTRtsp53-hygro and Susanne Gollin for karyotyping. We also thank Saleem Khan and Jim Pipas for comments on the manuscript. This work was supported by NIH grant HL33741 (to EVP)

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Authors and Affiliations

  1. Department of Pediatrics, Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pennsylvania, 15213, USA

    XiaoYing Yin, Linnette Grove & Edward V Prochownik

  2. Department of Pediatrics, Section of Hematology/Oncology, the University of Michigan Medical Center, Ann Arbor, 48109, Michigan, USA

    Nabanita S Datta & Michael W Long

  3. Department of Molecular Genetics and Biochemistry, the University of Pittsburgh Medical Center, Pittsburgh, 15213, Pennsylvania, USA

    Edward V Prochownik

  4. The University of Pittsburgh Cancer Institute, Pittsburgh, 15213, Pennsylvania, USA

    Edward V Prochownik

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Yin, X., Grove, L., Datta, N. et al. C-myc overexpression and p53 loss cooperate to promote genomic instability. Oncogene 18, 1177–1184 (1999). https://doi.org/10.1038/sj.onc.1202410

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