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Merkel cell polyomavirus small t antigen induces cancer and embryonic merkel cell proliferation in a transgenic mouse model

Shuda, M and Guastafierro, A and Geng, X and Shuda, Y and Ostrowski, SM and Lukianov, S and Jenkins, FJ and Honda, K and Maricich, SM and Moore, PS and Chang, Y (2015) Merkel cell polyomavirus small t antigen induces cancer and embryonic merkel cell proliferation in a transgenic mouse model. PLoS ONE, 10 (11).

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Abstract

© 2015 Shuda et al. 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. Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro. To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT: Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shuda, Mmas253@pitt.eduMAS253
Guastafierro, A
Geng, Xxuehui@pitt.eduXUEHUI
Shuda, Yyos21@pitt.eduYOS21
Ostrowski, SM
Lukianov, S
Jenkins, FJfjenkins@pitt.eduFJENKINS
Honda, K
Maricich, SM
Moore, PSpsm9@pitt.eduPSM9
Chang, Yyc70@pitt.eduYC70
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorChen, SuzieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 6 November 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0142329
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Date Deposited: 23 Aug 2016 14:45
Last Modified: 02 Nov 2018 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/28365

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