Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Tracy D

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Merkel Cell Polyomavirus Small T Antigen Is Oncogenic in Transgenic Mice Monique E. Verhaegen, Doris Mangelberger, Paul W. Harms, Tracy D. Vozheiko, Jack W. Weick, Dawn M. Wilbert, Thomas L. Saunders, Alexandre N. Ermilov, Christopher K. Bichakjian, Timothy M. Johnson, Michael J. Imperiale, Andrzej A. Dlugosz Journal of Investigative Dermatology Volume 135, Issue 5, Pages 1415-1424 (May 2015) DOI: 10.1038/jid.2014.446 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Epithelial transformation in preterm mouse embryo expressing MCPyV sTAg. (a) Transgenic cassette including bovine keratin 5 (K5) promoter, wild-type Merkel cell polyomavirus (MCPyV) small T antigen (sTAg), and internal ribosomal entry site (IRES)-tdTomato (RFP), designated K5-sTAg. (b) Histology of indicated epithelia from preterm control and K5-sTAg embryos. Rectangles indicate regions shown at higher magnification. Note: increased thickness of epithelia in K5-sTAg mice and loss or reduction of differentiated granular (white asterisk) and cornified (black asterisk) cell layers seen in controls. White arrowheads indicate pyknotic nuclei with condensed chromatin suggestive of apoptosis in K5-sTAg epithelia; black arrowheads identify suprabasal mitotic figures, which are normally restricted to basal or immediate suprabasal cell layers. Scale bars=25 μm. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 MCPyV sTAg alters epithelial differentiation, proliferation, and apoptosis. (a) Hematoxylin and eosin (H&E) and red fluorescent protein (RFP) immunostaining of acral skin and tongue showing disorganized, hyperplastic epithelia, and widespread transgene (RFP) expression. (b) Expansion of the basal layer marker keratin 5 (K5) and impaired expression of the granular cell marker loricrin in sTAg-expressing epithelia. (c) Striking upward expansion of Ki67-expressing proliferating cells and phospho-histone H3 (pHH3)-expressing mitotic cells in sTAg-expressing epidermis. (d) Immunostaining for the apoptosis marker CC3 and DNA damage response marker γH2AX in sTAg epidermis. Scale bars=25 μm. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Epithelial transformation by a protein phosphatase 2A (PP2A) binding–deficient sTAg mutant. (a) Keratin 5 (K5)-sTAgL142A transgene construction identical to K5-sTAg in Figure 1a, except for L142A substitution, which blocks sTAg binding to PP2A. (b) Hematoxylin and eosin and RFP immunostaining in sections from acral skin, tongue, and palate, showing features of transformation similar to those in K5-sTAg mice and robust transgene expression. RFP immunostaining is shown in insets. Scale bars=50 μm. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Lack of epithelial transformation by an LSD sTAg mutant. (a) Transgene construction identical to K5-sTAg in Figure 1a, except for 91–95A substitutions, which block sTAg binding to Fbxw7. (b) Similar histology of acral skin and tongue in sections from control and K5-sTAg91-95A transgenic mice, despite robust RFP expression in basal layer cells of transgenic mice. (c) Similar profile of epidermal markers and proliferation and lack of CC3 and γH2AX immunostaining in control and K5-sTAg91–95A transgenic acral skin. Scale bars=50 μm. H&E, hematoxylin and eosin; K5, keratin 5; LTAg, large T antigen; RFP, red fluorescent protein; sTAg, small T antigen. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Postnatal activation of sTAg induces epidermal transformation in adult mice. (a) Design of KLEsT transgene expressing eGFP and dormant sTAg, in which Cre-mediated recombination and GFP excision allow keratin 5 (K5)-driven sTAg expression. (b, c) Phenotype of K5-CreER;KLEsT (iK5;KLEsT) bitransgenic mice 2–3 weeks post tamoxifen treatment at P21. Note massive epidermal hyperplasia, disorganized stratification, suprabasal mitoses (arrowheads), and hyperkeratotic regions (asterisk). (d) Quantification of increased epidermal thickness at indicated sites (N=3 for each column, error bars indicate SEM, **P<0.005, ***P<0.0003). (e) Similarity of iK5;KLEsT epidermal phenotype and human SCC in situ. Both lesions show a severely disorganized epithelium, pale-staining atypical epidermal cells (arrowheads), apoptotic cells (arrows), and hyperkeratosis (asterisk). (f) Expression of sTAg in lysates from iK5;KLEsT mice collected 11 days (snout) and 21 days (tail) after tamoxifen treatment. sTAg was detected by immunoprecipitation and immunoblotting using 2t2 monoclonal Ab. Scale bars=50 μm. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Postnatal activation of sTAg induces markers of epidermal transformation and accumulation of Fbxw7 target proteins. (a) Expansion of proliferative cell layers (Ki67), increased apoptosis (cleaved caspase 3; CC3), and DNA damage (γH2AX) in tail epidermis of sTAg-expressing iK5;KLEsT mice 3 weeks after treatment with tamoxifen. (b) Expansion of cell layers expressing keratin 5 (K5) and focal reductions in expression of the differentiation markers K10 and loricrin. (c) Upregulation of hyperplasia-associated keratins K6 and K17 in the epidermis of iK5;KLEsT mice. Normal expression of these keratins is largely restricted to the hair follicle. (d) Immunoblotting for Fbwx7 targets, proliferating cell nuclear antigen (PCNA), K17, and GFP in sets of snout lysates from control and iK5;KLEsT mice, collected 24 days (left panels) or 28 days (right panels) after tamoxifen treatment. Loss of GFP expression confirms efficient recombination of the KLEsT transgene. Scale bars=50 μm. Journal of Investigative Dermatology 2015 135, 1415-1424DOI: (10.1038/jid.2014.446) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions