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Mutant p53 and genomic instability in a transgenic mouse model of breast cancer

Oncogene volume 19, pages 1045–1051 (2000)Cite this article

Tumorigenesis is a multistage process involving multiple genetic aberrations (Fearon and Vogelstein, 1990). These aberrations may include mutations in cellular proto-oncogenes that constitutively activate a growth signal transduction pathway, inactivation of tumor suppressor genes, and inactivation of genes that promote cell death. Other mutations provide an indirect growth advantage by compromising the genetic stability of the cell, increasing the occurrence of subsequent genetic lesions (Tlsty et al., 1995). Each successive mutation may then enhance the tumorigenic potential of the cell (Nowell, 1976). Advances in transgenic and knockout technologies make it possible to genetically engineer mice to mimic the individual steps in this process in order to better understand events contributing to cancer progression at the molecular level. Specifically, mouse models prone to genetic instability have been generated that may be useful to screen for early molecular events involved in carcinogenesis.

p53 is the most commonly mutated gene in human cancers, with approximately 40% of tumors displaying some alteration in p53 (Osborne et al., 1991). Unlike deletion or nonsense mutations observed in other tumor-suppressor genes, most p53 alterations are missense mutations resulting in the expression of a functionally altered protein (Hainaut et al., 1997). Wild-type p53 has been called the `guardian of the genome,' as p53 responds to DNA damage or checkpoint failure by either arresting the cell in the G1 phase of the cell cycle for damage repair or through the initiation of an apoptotic pathway to eliminate the damaged cell entirely (Lane, 1992). Wild-type p53 is particularly critical for the maintenance of genomic stability; aberrant ploidy, gene amplification, increased recombination, and centrosomal dysregulation have been observed in cells lacking p53 (Donehower, 1997). Mutations in p53 may result not only in a loss of wild-type function, but also in the generation of dominant-negative and gain-of-function mutants (e.g., Dittmer et al. (1993)).

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Acknowledgements

This research was supported by grant CA 16303 from the National Institutes of Health. KL Murphy was supported in part by Cell and Molecular Biology Interdisciplinary Program training grant GM08231. The authors would like to thank Dr Rodolfo Laucirica for help with FACS analysis and Drs Daniel Medina, Darryl Hadsell, and Bill Brinkley for valuable discussions. We would further like to thank Dr Thea Goepfert, Jeannie Zhong, and Frank Herbert for help with centrosome staining and confocal microscopy.

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  1. Cell and Molecular Biology Program, Baylor College of Medicine, Houston, 77030, TX, USA

    Kristen L Murphy

  2. Department of Cell Biology, Baylor College of Medicine, Houston, 77030, TX, USA

    Kristen L Murphy & Jeffrey M Rosen

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Murphy, K., Rosen, J. Mutant p53 and genomic instability in a transgenic mouse model of breast cancer. Oncogene 19, 1045–1051 (2000). https://doi.org/10.1038/sj.onc.1203274

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