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The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models

Oncogene volume 26, pages 2964–2974 (2007)Cite this article

Abstract

Human p53, unlike mouse p53, contains a polymorphic site at codon 72 in exon 4 encoding either an arginine amino acid (72R) or a proline residue (72P). The 72R form was shown to induce apoptosis better than the 72P form, partly owing to its ability to efficiently bind to the nuclear-export protein CRM1 and localize to the mitochondria. This polymorphism has also been associated with cancer predisposition and chemo-sensitivity. Further understanding of the in vivo significance of this polymorphism in carcinogenesis requires the generation of mouse models. We have thus evaluated if the polymorphism-specific effects of human p53 are retained in mouse cells. Though being transcriptionally active, both the human polymorphs were found to have lost their ability to differentially suppress growth and bind to CRM1 or MDM2 in mouse cells. Moreover, chimaeric proteins containing mouse exons 2–3 and human exons 4–11 have also lost the polymorphism-specific effects in human cells, suggesting that human exons 2–3 are important in regulating the polymorphism-specific effects. Furthermore, human p53 and the various chimaeric proteins were generally less effective in inhibiting growth of mouse cells compared to mouse p53, suggesting that mouse p53 is more potent than human p53 in suppressing growth, partly due to enhanced binding of MDM2 to human p53. The data together suggest that mouse cells may not provide an appropriate environment for the manifestation of the polymorphism-specific functional differences of human p53, and hence, cautions against the expression of full-length or chimaeric p53 proteins in mice to study the effects of the polymorphism.

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Acknowledgements

We thank Dr Kenneth Lee for critical reading of the paper and the National Medical Research Council, Singapore, for their generous funding and support to KS.

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Authors and Affiliations

  1. Division of Cellular and Molecular Research, Laboratory of Molecular Carcinogenesis, National Cancer Centre, Singapore, Singapore

    B H Phang & K Sabapathy

  2. Department of Biochemistry, National University of Singapore, Singapore, Singapore

    K Sabapathy

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  1. B H Phang
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Correspondence to K Sabapathy.

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Phang, B., Sabapathy, K. The codon 72 polymorphism-specific effects of human p53 are absent in mouse cells: implications on generation of mouse models. Oncogene 26, 2964–2974 (2007). https://doi.org/10.1038/sj.onc.1210112

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