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Role of a p53 polymorphism in the development of human papilloma-virus-associated cancer

The E6 oncoprotein derived from tumour-associated human papillomaviruses (HPVs) binds to and induces the degradation of the cellular tumour-suppressor protein p53. A common polymorphism that occurs in the p53 amino-acid sequence results in the presence of either a proline or an arginine at position 72. The effect of this polymorphism on the susceptibility of p53 to E6-mediated degradation has been investigated and the arginine form of p53 was found to be significantly more susceptible than the proline form. Moreover, allelic analysis of patients with HPV-associated tumours revealed a striking overrepresentation of homozygous arginine-72 p53 compared with the normal population, which indicated that individuals homozygous for arginine 72 are about seven times more susceptible to HPV-associated tumorigenesis than heterozygotes. The arginine-encoding allele therefore represents a significant risk factor in the development of HPV-associated cancers.

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Figure 1: Comparison of the rate of HPV-18 E6 mediated degradation of p53Pro and p53Arg in vitro.
Figure 2: Comparison of HPV-18 E6 induced degradation of p53Pro and p53Arg in vivo.
Figure 3: HPV-16 and HPV-11 E6 preferentially target p53Arg over p53Pro for degradation in vivo.
Figure 4: HPV-16 E6-induced degradation of p53Pro and p53Arg is mediated by the proteasome.
Figure 5: Comparison of the susceptibility of p53 to E6-mediated degradation in a cell line containing endogenous p53Pro and p53Arg alleles and HPV-.16 E6.
Figure 6: PCR detection of p53 alleles.

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Acknowledgements

We thank P. Spink for assistance with the development of HPV screening and typing; I. Jacobs and H. Stevens for cervical and normal DNA; D. Pim for comments on the manuscript; and A.Norman for statistical analysis. G.M. acknowledges the support from the National Cancer Institute of Canada with funds from the Canadian Cancer Society and NSERC. C.H. is the recipient of a MRC Clinical Training Fellowship. G.M., A.S. and L.B. thank L. Crawford for insightful discussions.

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Correspondence to Greg Matlashewski or Lawrence Banks.

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Storey, A., Thomas, M., Kalita, A. et al. Role of a p53 polymorphism in the development of human papilloma-virus-associated cancer. Nature 393, 229–234 (1998). https://doi.org/10.1038/30400

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