Cargando…
Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein
The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cy...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386700/ https://www.ncbi.nlm.nih.gov/pubmed/28061478 http://dx.doi.org/10.18632/oncotarget.14469 |
_version_ | 1782520820704215040 |
---|---|
author | Marsh, Elizabeth K. Delury, Craig P. Davies, Nicholas J. Weston, Christopher J. Miah, Mohammed A.L. Banks, Lawrence Parish, Joanna L. Higgs, Martin R Roberts, Sally |
author_facet | Marsh, Elizabeth K. Delury, Craig P. Davies, Nicholas J. Weston, Christopher J. Miah, Mohammed A.L. Banks, Lawrence Parish, Joanna L. Higgs, Martin R Roberts, Sally |
author_sort | Marsh, Elizabeth K. |
collection | PubMed |
description | The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification. |
format | Online Article Text |
id | pubmed-5386700 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53867002017-04-26 Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein Marsh, Elizabeth K. Delury, Craig P. Davies, Nicholas J. Weston, Christopher J. Miah, Mohammed A.L. Banks, Lawrence Parish, Joanna L. Higgs, Martin R Roberts, Sally Oncotarget Research Paper The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification. Impact Journals LLC 2017-01-03 /pmc/articles/PMC5386700/ /pubmed/28061478 http://dx.doi.org/10.18632/oncotarget.14469 Text en Copyright: © 2017 Marsh et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Marsh, Elizabeth K. Delury, Craig P. Davies, Nicholas J. Weston, Christopher J. Miah, Mohammed A.L. Banks, Lawrence Parish, Joanna L. Higgs, Martin R Roberts, Sally Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title | Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title_full | Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title_fullStr | Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title_full_unstemmed | Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title_short | Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein |
title_sort | mitotic control of human papillomavirus genome-containing cells is regulated by the function of the pdz-binding motif of the e6 oncoprotein |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386700/ https://www.ncbi.nlm.nih.gov/pubmed/28061478 http://dx.doi.org/10.18632/oncotarget.14469 |
work_keys_str_mv | AT marshelizabethk mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT delurycraigp mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT daviesnicholasj mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT westonchristopherj mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT miahmohammedal mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT bankslawrence mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT parishjoannal mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT higgsmartinr mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein AT robertssally mitoticcontrolofhumanpapillomavirusgenomecontainingcellsisregulatedbythefunctionofthepdzbindingmotifofthee6oncoprotein |