title: Merkel Cell Polyomavirus Small T Antigen Induces Cancer and Embryonic Merkel Cell Proliferation in a Transgenic Mouse Model.
abstract: 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 and 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.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shuda
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Guastafierro
authors.affiliation: Richard King Mellon Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Geng
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shuda
authors.affiliation: Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ostrowski
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lukianov
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Jenkins
authors.affiliation: Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Kord
authors.initials: K
authors.lastname: Honda
authors.affiliation: Richard King Mellon Institute for Pediatric Research, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Maricich
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
mesh_terms: D000708:Anaplasia; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D015266:Carcinoma, Merkel Cell / Q000473:pathology* / Q000821:virology; D002452:Cell Count; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000473:pathology*; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D018862:Merkel Cells / Q000473:pathology*; D059965:Merkel cell polyomavirus / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D012878:Skin Neoplasms / Q000473:pathology* / Q000821:virology; D013154:Spleen / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D000957:Antigens, Viral, Tumor; D016159:Tumor Suppressor Protein p53