Evolution of HPV E6 function and the association with cancer
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High-risk HPV infection is thought to be necessary and the major cause of cervical cancer. To identify the oncogenic functions of HPV E6 protein, we evaluated evolutionary related high-risk (HPV56, HPV66) and low-risk (HPV53) types from a single HPV species group.;HPV56 and HPV66 positive samples from the population-based Guanacaste study were classified into 3 and 2 main variant lineages, respectively. HPV56 variant A was found to be associated with increased cytologic abnormalities compared to variants B and C (P=0.038). Representative samples from each variant lineage of HPV56 and HPV66 were cloned and sequenced. Although HPV56 E6 ORF had the highest dN/dS ratio (1.07) in the HPV56 genome, ectopic expression of E6 from each variant lineage indicated that there was no difference in the degradation of p53.;The E6 ORFs from 27 HPV types representing members of all HPV alpha species groups were cloned and tested using an in vivo assay to measure E6 induced p53 degradation. Expression of E6 from all epidemiologically high-risk types and several types not associated with cancer (i.e., HPV53, HPV70, HPV71 and HPV73) significantly reduced p53 levels. p53 degradation was highly correlated with the topology of a tree created from the early genes. This indicates that the E6 protein's ability to degrade p53 is an evolved phenotype inherited from an ancestor of high-risk species. Unexpectedly, HPV71 E6 induced p53 degradation, but did not share this common ancestor. Alignment of the E6 ORFs identified one variable amino acid position corresponding to HPV 16 E6 T 17 that was highly correlated with the ability to degrade p53. Types that did not degrade p53 (except HPV40) have either Lysine (K) or Arginine (R) at this position, whereas p53 degraders did not. Alteration of this amino acid in HPV71 E6 changed it from a p53 degrader to a non-degrader, while alteration of the corresponding site in HPV90 and HPV 106 E6s converted them from p53 non-degraders to degraders.;Conclusion: HPV E6 induced p53 degradation is an evolved phenotype, whether this phenotype is critical for cancer development or is a manifestation of evolution remains to be determined.