A Drosophila Model of HPV E6-Induced Malignancy Reveals Essential Roles for Magi and the Insulin Receptor

PLoS Pathogens

Mary Gilbert¹  Mojgan Padash Barmchi²  Lawrence Banks²  Miranda Thomas³  Vanessa J. Auld⁴  Bing Zhang⁴ 

[1] Department of Biology, University of Oklahoma, Norman, Oklahoma, United States of America;Department of Zoology, University of British Columbia, Vancouver, Canada;Division of Biological Sciences, University of Missouri, Columbia, Missouri, United States of America;International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

关键词: Eyes;    Drosophila melanogaster;    Apoptosis;    Insulin signaling;    Insulin;    Phenotypes;    Carcinogenesis;    Imaginal discs;   

DOI  :  10.1371/journal.ppat.1005789

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY