title: A Drosophila Model of HPV E6-Induced Malignancy Reveals Essential Roles for Magi and the Insulin Receptor.
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.
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, Canada.|Department of Biology, University of Oklahoma, Norman, Oklahoma, United States of America.|Division of Biological Sciences, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Padash Barmchi
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, Canada.
authors.forename: Mary
authors.initials: M
authors.lastname: Gilbert
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Miranda
authors.initials: M
authors.lastname: Thomas
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
authors.affiliation: Department of Biology, University of Oklahoma, Norman, Oklahoma, United States of America.|Division of Biological Sciences, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, Canada.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Auld
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002472:Cell Transformation, Viral / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D006801:Humans; D007150:Immunohistochemistry; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D011972:Receptor, Insulin; D009703:Nucleoside-Phosphate Kinase; C472856:MAGI protein, Drosophila