Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
PLoS One. 2010 Sep 17;5(9):e12816. doi: 10.1371/journal.pone.0012816.
Human Papillomavirus (HPV) E6 induced p53 degradation is thought to be an essential activity by which high-risk human Alphapapillomaviruses (alpha-HPVs) contribute to cervical cancer development. However, most of our understanding is derived from the comparison of HPV16 and HPV11. These two viruses are relatively distinct viruses, making the extrapolation of these results difficult. In the present study, we expand the tested strains (types) to include members of all known HPV species groups within the Alphapapillomavirus genus.
We report the biochemical activity of E6 proteins from 27 HPV types representing all alpha-HPV species groups to degrade p53 in human cells. Expression of E6 from all HPV types epidemiologically classified as group 1 carcinogens significantly reduced p53 levels. However, several types not associated with cancer (e.g., HPV53, HPV70 and HPV71) were equally active in degrading p53. HPV types within species groups alpha 5, 6, 7, 9 and 11 share a most recent common ancestor (MRCA) and all contain E6 ORFs that degrade p53. A unique exception, HPV71 E6 ORF that degraded p53 was outside this clade and is one of the most prevalent HPV types infecting the cervix in a population-based study of 10,000 women. Alignment of E6 ORFs identified an amino acid site that was highly correlated with the biochemical ability to degrade p53. Alteration of this amino acid in HPV71 E6 abrogated its ability to degrade p53, while alteration of this site in HPV71-related HPV90 and HPV106 E6s enhanced their capacity to degrade p53.
These data suggest that the alpha-HPV E6 proteins' ability to degrade p53 is an evolved phenotype inherited from a most recent common ancestor of the high-risk species that does not always segregate with carcinogenicity. In addition, we identified an amino-acid residue strongly correlated with viral p53 degrading potential.
人乳头瘤病毒（HPV）E6 诱导 p53 降解被认为是高危型人乳头瘤病毒（alpha-HPV）促进宫颈癌发展的重要活性。然而，我们的大部分认识都来自于 HPV16 和 HPV11 的比较。这两种病毒是相对不同的病毒，使得这些结果的推断变得困难。在本研究中，我们扩大了测试的菌株（类型），包括 Alpha 乳头瘤病毒属中所有已知 HPV 种组的成员。
我们报告了来自 27 种 HPV 类型的 E6 蛋白的生化活性，这些 HPV 类型代表了所有 alpha-HPV 种组，可在人类细胞中降解 p53。从所有 HPV 类型中表达的 E6 蛋白，这些 HPV 类型在流行病学上被归类为致癌物质 1 组，显著降低了 p53 水平。然而，几种与癌症无关的类型（例如 HPV53、HPV70 和 HPV71）同样具有降解 p53 的活性。种组 alpha5、6、7、9 和 11 中的 HPV 类型具有最近的共同祖先（MRCA），并且都包含降解 p53 的 E6 ORF。一个独特的例外是 HPV71 E6 ORF 降解 p53 的氨基酸位点，它不在这个分支之外，并且是在一项对 10000 名女性进行的基于人群的研究中感染宫颈的最常见 HPV 类型之一。E6 ORF 的比对确定了一个与生化降解 p53能力高度相关的氨基酸位点。HPV71 E6 中的这个氨基酸的改变使其失去了降解 p53 的能力，而 HPV71 相关 HPV90 和 HPV106 E6 中的这个位点的改变增强了它们降解 p53 的能力。
这些数据表明，alpha-HPV E6 蛋白降解 p53 的能力是一种从高危种的最近共同祖先继承而来的进化表型，并不总是与致癌性相关。此外，我们确定了一个与病毒 p53 降解潜力密切相关的氨基酸残基。
