Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice
Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, MCPyV, and MCC tumor cells express putative polyomavirus oncoproteins small T antigen (sTAg) and truncated large T antigen (tLTAg). Here, we show robust transfo...
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| Format: | Online |
| Language: | English |
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2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397111/ |
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pubmed-43971112015-11-01 Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice Verhaegen, Monique E. Mangelberger, Doris Harms, Paul W. Vozheiko, Tracy D. Weick, Jack W. Wilbert, Dawn M. Saunders, Thomas L. Ermilov, Alexandre N. Bichakjian, Christopher K. Johnson, Timothy M. Imperiale, Michael J. Dlugosz, Andrzej A. Article Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, MCPyV, and MCC tumor cells express putative polyomavirus oncoproteins small T antigen (sTAg) and truncated large T antigen (tLTAg). Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models. Epithelia of pre-term sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation and apoptosis, and activation of a DNA damage response. Epithelial transformation did not require sTAg interaction with the PP2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently-described sTAg domain that binds Fbxw7, the substrate-binding component of the SCF ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins. Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies. Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation. 2014-10-14 2015-05 /pmc/articles/PMC4397111/ /pubmed/25313532 http://dx.doi.org/10.1038/jid.2014.446 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Verhaegen, Monique E. Mangelberger, Doris Harms, Paul W. Vozheiko, Tracy D. Weick, Jack W. Wilbert, Dawn M. Saunders, Thomas L. Ermilov, Alexandre N. Bichakjian, Christopher K. Johnson, Timothy M. Imperiale, Michael J. Dlugosz, Andrzej A. |
| spellingShingle |
Verhaegen, Monique E. Mangelberger, Doris Harms, Paul W. Vozheiko, Tracy D. Weick, Jack W. Wilbert, Dawn M. Saunders, Thomas L. Ermilov, Alexandre N. Bichakjian, Christopher K. Johnson, Timothy M. Imperiale, Michael J. Dlugosz, Andrzej A. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice |
| author_facet |
Verhaegen, Monique E. Mangelberger, Doris Harms, Paul W. Vozheiko, Tracy D. Weick, Jack W. Wilbert, Dawn M. Saunders, Thomas L. Ermilov, Alexandre N. Bichakjian, Christopher K. Johnson, Timothy M. Imperiale, Michael J. Dlugosz, Andrzej A. |
| author_sort |
Verhaegen, Monique E. |
| title |
Merkel cell polyomavirus small T antigen is oncogenic in transgenic
mice |
| title_short |
Merkel cell polyomavirus small T antigen is oncogenic in transgenic
mice |
| title_full |
Merkel cell polyomavirus small T antigen is oncogenic in transgenic
mice |
| title_fullStr |
Merkel cell polyomavirus small T antigen is oncogenic in transgenic
mice |
| title_full_unstemmed |
Merkel cell polyomavirus small T antigen is oncogenic in transgenic
mice |
| title_sort |
merkel cell polyomavirus small t antigen is oncogenic in transgenic
mice |
| description |
Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor
frequently associated with clonal integration of a polyomavirus, MCPyV, and MCC tumor
cells express putative polyomavirus oncoproteins small T antigen (sTAg) and truncated
large T antigen (tLTAg). Here, we show robust transforming activity of sTAg in
vivo in a panel of transgenic mouse models. Epithelia of pre-term
sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased
proliferation and apoptosis, and activation of a DNA damage response. Epithelial
transformation did not require sTAg interaction with the PP2A protein complex, a tumor
suppressor in some other polyomavirus transformation models, but was strictly dependent on
a recently-described sTAg domain that binds Fbxw7, the substrate-binding component of the
SCF ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene
also led to epithelial transformation with development of lesions resembling squamous cell
carcinoma in situ and elevated expression of Fbxw7 target proteins. Our
data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic
transformation in vivo, implicating sTAg as an oncogenic driver in MCC
and perhaps other human malignancies. Moreover, the loss of transforming activity
following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in
vivo transformation. |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397111/ |
| _version_ |
1613211758944583680 |