Abstract
Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus which is the primary causative agent of cervical cancer. Cell transformation arises from deregulated expression of the E6 and E7 oncogenes. E6 has been shown to bind a number of cellular proteins, including p53 and proteins containing a PDZ domain. This study reports the first RNA aptamers to E6. These have been employed as molecular tools to further investigate E6-p53 and E6-PDZ interactions. This study is focussed on two aptamers (termed F2 and F4) which induced apoptosis in cells derived from an HPV16-transformed cervical carcinoma. The molecules were able to inhibit the interaction between E6 and PDZ1 from Magi1, with F2 being the most effective inhibitor. Neither of the aptamers inhibited E6-p53 interaction or p53 degradation. This study shows the specificity of this approach and highlights the potential benefits of the E6 aptamers as potential therapeutic or diagnostic agents in the future.
Highlights
Human papillomaviruses (HPVs) are DNA tumour viruses that infect epithelial cells
We have described an RNA aptamer to Human papillomavirus 16 (HPV16) E6 that inhibits the interaction between E6 and the
This molecule (F2) is the most apoptotic of the aptamers in SiHa cells, appears to have no effect on p53 degradation. It appears that the apoptosis observed occurs via a p53-independent pathway, e.g., via BCL-2 family members, further work e.g., analysis of steady state levels of p53 in SiHa cells could be useful in order to confirm this finding
Summary
Human papillomaviruses (HPVs) are DNA tumour viruses that infect epithelial cells. More than 100 types have been identified and those which infect genital epithelia are classified as low- or high-risk, depending on the risk of development of cancer [1,2]. E6 has been shown to promote degradation of the tumour suppressor p53 by interacting with the E3 ubiquitin ligase, E6-AP [8,9] while E7 has been demonstrated to bind and destabilise the cell cycle control protein pRb [10,11]. In addition to these well characterised roles, E6 and E7 interact with at least 50 other cellular proteins (for reviews see [12,13])
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