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

Nature Genetics volume 33, pages 357–365 (2003)Cite this article

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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Figure 1: The Arg72 variant of p53 is a better inducer of apoptosis than is Pro72.
Figure 2: The Arg72 variant of p53 is a better inducer of apoptosis in cell lines with inducible and endogenous p53.
Figure 3: The Pro72 and Arg72 variants have similar transcriptional potential.
Figure 4: The Arg72 variant shows greater localization to the mitochondria after temperature shift and greater translocation of cytochrome c to the cytosol.
Figure 5: The Arg72 variant shows enhanced interaction with the mitochondrial proteins GRP75 and Hsp60 but not with the nuclear protein mSin3a.
Figure 6: The Arg72 variant shows greater interaction with the nuclear-export protein CRM1 and greater interaction with and ubiquitination by the E3 ubiquitin ligase MDM2.
Figure 7: Mitochondrial p53 is ubiquitinated.

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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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  1. Patrick Dumont and J. I-Ju Leu: These authors contributed equally to this work.

Authors and Affiliations

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

    Patrick Dumont, Anthony C. Della Pietra III & Maureen Murphy

  2. Department of Genetics, University of Pennsylvania School of Medicine, 422 Curie Blvd., Philadelphia, 19104, Pennsylvania, USA

    J. I-Ju Leu & Donna L. George

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Correspondence to Maureen Murphy.

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Dumont, P., Leu, JJ., Della Pietra, A. et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33, 357–365 (2003). https://doi.org/10.1038/ng1093

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