Abstract
Cervical cancer is one of the leading causes of cancer death in women worldwide. The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation, activities that are believed to contribute towards malignancy. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown. We have developed an in vivo model of HPV E6-mediated cellular transformation using the genetic model organism, Drosophila melanogaster. Co-expression of E6 and human UBE3A in wing and eye epithelia results in severe morphological abnormalities. Furthermore, E6, via its PDZ-binding motif and in cooperation with UBE3A, targets a suite of PDZ proteins that are conserved in human and Drosophila, including Magi, Dlg and Scribble. Similar to human epithelia, Drosophila Magi is a major degradation target. Magi overexpression rescues the cellular abnormalities caused by E6+UBE3A coexpression and this activity of Magi is PDZ domain-dependent. Drosophila p53 was not targeted by E6+UBE3A, and E6+UBE3A activity alone is not sufficient to induce tumorigenesis, which only occurs when E6+UBE3A are expressed in conjunction with activated/oncogenic forms of Ras or Notch. Finally, through a genetic screen we have identified the insulin receptor signaling pathway as being required for E6+UBE3A induced hyperplasia. Our results suggest a highly conserved mechanism of HPV E6 mediated cellular transformation, and establish a powerful genetic model to identify and understand the cellular mechanisms that underlie HPV E6-induced malignancy.
Highlights
Cervical cancer is the fourth leading cause of cancer death in women worldwide with ~500,000 new cases of cervical cancer annually and ~250,000 deaths worldwide
The E6 oncoprotein encoded by human papillomaviruses (HPVs) has been implicated in the progression of primary tumors to metastatic disease and we have developed a new model in the fruit fly (Drosophila melanogaster) to study the cellular effects of E6
We show that coexpression of HPV E6 and human UBE3A/E6AP in the wing and eye results in severe morphological defects, whereas E6 or UBE3A expression alone results in none
Summary
Cervical cancer is the fourth leading cause of cancer death in women worldwide with ~500,000 new cases of cervical cancer annually and ~250,000 deaths worldwide. The main causative agents of cervical cancer are the high-risk human papillomaviruses (HPVs). E6 inactivates a range of targets including the tumor suppressor protein p53 and important polarity regulators including hDlg, Scribble/Vartul and MAGI-1, all of which are directed for ubiquitin-mediated proteasomal degradation [14,15,16,17,18,19]. E6 directs the degradation of many of its substrates through recruitment of an E3 ubiquitin ligase, UBE3A/E6AP, with which it forms a stable complex and redirects its activity towards the different E6 target proteins [20,21]. Multiple functions of E6, including interaction with UBE3A, p53 and PDZ domain-containing substrates, appear to be required for its ability to bring about cell transformation and to contribute towards malignancy in animal models
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