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The codon 72 polymorphic variants of p53 have markedly different apoptotic potential

Nature Genetics volume 33, pages 357365 (2003) | Download Citation

Abstract

The gene TP53, encoding p53, has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. This polymorphism occurs in the proline-rich domain of p53, which is necessary for the protein to fully induce apoptosis. We found that in cell lines containing inducible versions of alleles encoding the Pro72 and Arg72 variants, and in cells with endogenous p53, the Arg72 variant induces apoptosis markedly better than does the Pro72 variant. Our data indicate that at least one source of this enhanced apoptotic potential is the greater ability of the Arg72 variant to localize to the mitochondria; this localization is accompanied by release of cytochrome c into the cytosol. These data indicate that the two polymorphic variants of p53 are functionally distinct, and these differences may influence cancer risk or treatment.

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Acknowledgements

The authors would like to thank J. Skipworth for technical assistance, A. Ganguly and C. Spittle for genotyping the melanoma and fibroblast cell lines and J. Boyd for confocal expertise. This work was supported by US Public Health Service National Cancer Institute grants to D.L.G. and M.M.

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Author notes

    • Patrick Dumont
    •  & J. I-Ju Leu

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111, USA.

    • Patrick Dumont
    • , Anthony C. Della Pietra III
    •  & Maureen Murphy
  2. Department of Genetics, University of Pennsylvania School of Medicine, 422 Curie Blvd., Philadelphia, Pennsylvania 19104, USA.

    • J. I-Ju Leu
    •  & Donna L. George

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The authors declare no competing financial interests.

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Correspondence to Maureen Murphy.

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DOI

https://doi.org/10.1038/ng1093