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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References
zur Hausen, H. & Schneider, A. in The Papovaviridae (eds Salzman, N. P. & Howley, P. M.) 245–263 (Plenum, New York, (1987)).
Dyson, N., Howley, P. M., Münger, K. & Harlow, E. The human papillomavirus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934–936 (1989).
Scheffner, M., Werness, B. A., Huibregste, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
Werness, B. A., Levine, A. J. & Howley, P. M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).
Crook, T., Wrede, D. & Vousden, K. H. p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6, 873–875 (1991).
Scheffner, M., Münger, K., Byrne, J. C. & Howley, P. M. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc. Natl Acad. Sci. USA 88, 5523–5527 (1991).
Vogelstein, B. & Kinzler, K. W. p53 function and dysfunction. Cell 70, 523–526 (1992).
Medcalf, E. A. & Milner, J. Targeting and degradation of p53 by E6 of human papillomavirus type 16 is preferential for the 1620+ p53 conformation. Oncogene 8, 2847–2851 (1993).
Marston, N. J., Crook, T. & Vousden, K. H. Interaction of p53 with MDM2 is independent of E6 and does not mediate wild type transformation suppressor function. Oncogene 9, 2707–2716 (1994).
Thomas, M., Massimi, P., Jenkins, J. & Banks, L. HPV-18 E6 mediated inhibition of p53 binding activity is independent of E6 induced degradation. Oncogene 10, 261–268 (1995).
Matlashewski, G. J. et al. Primary structure polymorphism at amino acid residue 72 of human p53. Mol. Cell. Biol. 7, 961–963 (1987).
Birgander, R. et al. P53 polymorphisms and haplotypes in lung cancer. Carcinogenesis 16, 2233–2236 (1995).
Moreau, F. & Matlashewski, G. Molecular analysis of different allelic variants of wild-type human p53. Biochem. Cell. Biol. 70, 1014–1019 (1992).
Crook, T., Ludwig, R. L., Marston, N., Willkomm, D. & Vousden, K. H. Sensitivity of p53 lysine mutants to ubiquitin-directed degradation targeted by human papillomavirus E6. Virology 217, 285–292 (1996).
Goldberg, A. The mechanism and function of ATP dependent proteases in bacterial and animal cells. Eur. J. Biochem. 203, 285–292 (1992).
Hershko, D. & Ciechanover, A. The ubiquitin system for protein degradation. Annu. Rev. Biochem. 61, 761–807 (1992).
Rock, K. et al. Inhibitors of the proteasome block degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761–771 (1994).
Milner, J. & Medcalf, E. A. Cotranslation of activated mutant p53 with wild type drives the wild type p53 into the mutant conformation. Cell 65, 765–774 (1991).
Sakamoto, H., Lewis, M. S., Kodama, H., Appella, E. & Sakaguchi, K. Specific sequences from the carboxy terminus of human p53 gene product form anti-parallel tetramers in solution. Proc. Natl Acad. Sci. USA 91, 8974–8978 (1994).
Androphy, E. J., Hubbert, N. L., Schiller, J. T. & Lowy, D. R. Identification ofthe HPV16 E6 protein from transformed mouse cells and human cervical carcinoma cell lines. EMBO J. 6, 989–992 (1987).
Butz, K. et al. Functional p53 protein in human papillomavirus-positive cancer cells. Oncogene 10, 927–936 (1995).
Fenteany, G. et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268, 726–731 (1995).
Zhang, W., Hu, G. & Deisseroth, A. Polymorphism at codon 72 of the p53 gene in human acute myelogenous leukemia. Gene 117, 271–275 (1992).
Vogan, K. et al. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res. 53, 5269–5273 (1993).
Beckman, G. et al. Is p53 polymorphism maintained by natural selection? Hum. Hered. 44, 266–270 (1994).
Weston, A. et al. Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer. Carcinogenesis 14, 583–587 (1994).
Murata, M. et al. Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history. Carcinogenesis 17, 261–264 (1996).
Kawajiri, K., Nakachi, K., Imai, K., Watanabe, J. & Hayashi, S. Germ line polymorphisma of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis 14, 1085–1089 (1993).
Jin, X. et al. Higher lung cancer risk for young African-Americans with the Pro/Pro p53 genotype. Carcinogenesis 16, 2205–2208 (1995).
Purdie, K. et al. Malignant transformation of cutaneous lesions in renal allograft patients: a role for human papillomavirus. Cancer Res. 53, 5328–5333 (1993).
Boyle, J., Briggs, J. D., Mackie, R. M., Junor, B. J. R. & Aitchison, T. C. Cancer, warts and sunshine in renal transplant patients. Cancer Res. 53, 5328–5333 (1993).
Blessing, K. et al. Histopathology of skin lesions in renal allograft recipients—an assessment of viral features and dysplasia. Histopathology 14, 129–139 (1989).
Benton, E. C. et al. in Immunodeficiency and the Skin (eds Fritsch, P., Schuler, G. & Hintner, H.) 168–177 (Karger, Basel, (1989)).
Glover, M. T., Proby, C. M. & Leigh, I. M. Skin cancer in renal transplant patients. Cancer Bull. 45, 220–224 (1993).
Shamanin, V. et al. Specific types of human papillomavirus found in benign proliferations and carcinomas of the skin in immunosuppressed patients. Cancer Res. 54, 4610–4613 (1994).
Berkhout, R. J. M. et al. Detection and typing of epidermodysplasia verruciformis-associated human papillomavirus types in cutaneous cancers from renal transplant recipients. J. Clin. Microbiol. 33, 690–695 ((1995)).
Shamanin, V. et al. Human papillomavirus infections in nonmelanoma skin cancer patients from renal transplant recipients and nonimmunosuppressed patients. J. Natl Canc. Inst. 88, 802–811 (1996).
Li, X. & Coffino, P. High-risk human papillomavirus E6 has two distinct binding sites within p53, of which only one determines degradation. J. Virol. 70, 4509–4516 (1996).
Walker, K. K. & Levine, A. J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc. Natl Acad. Sci. USA 93, 15335–15340 (1996).
Sakamuro, D., Sabbatini, P., White, E. & Prendergast, G. C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15, 887–898 (1997).
Yu, H. et al. Structural basis for the binding of proline-rich peptides to SH3 domains. Cell 76, 933–945 (1994).
Sun, X.-F. et al. Anovel p53 germline alteration identified in a late onset breast cancer kindred. Oncogene 13, 407–411 (1996).
Chittenden, T. et al. Aconserved domain in bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 14, 5589–5596 (1995).
Banks, L., Matlashewski, G. & Crawford, L. Isolation of human p53 specific monoclonal antibodies and their use in the study of human p53 expression. Eur. J. Biochem. 159, 529–534 (1986).
Manos, M. M. et al. The use of polymerase chain reaction amplification for the detection of genital human papillomaviruses. Cancer Cells 7, 209–214 (1989).
Snijders, P. J. et al. The use of general primers in the polymerase chain reaction permits the detection of a broad spectrum of human papillomavirus genotypes. J. Gen. Virol. 71, 173–181 (1990).
Shamanin, V., Delius, H. & de Villiers, E.-M. Development of a broad spectrum PCR assay for papillomaviruses and its application in screening lung cancer biopsies. J. Gen. Virol. 75, 1149–1156 (1994).
Chan, S.-Y., Delius, H., Halpern, A. L. & Bernard, H.-U. Analysis of genomic sequences of 95 papillomavirus types: uniting typing phylogeny and taxonomy. J. Virol. 69, 3074–3083 (1995).
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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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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DOI: https://doi.org/10.1038/30400
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