Merkel cell polyomavirus large T antigen binding to pRb promotes skin hyperplasia and tumor development

• Published in: PLoS pathogens Vol. 18; no. 5; p. e1010551
• Main Authors: Spurgeon, Megan E, Cheng, Jingwei, Ward-Shaw, Ella, Dick, Frederick A, DeCaprio, James A, Lambert, Paul F
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2022; Public Library of Science (PLoS)
• Subjects: Animals; Antigen (tumor-associated); Antigen T (large); Antigens; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Antigens, Viral, Tumor - genetics; Antigens, Viral, Tumor - metabolism; Binding; Biology and Life Sciences; Cancer; Carcinoma, Merkel Cell; Care and treatment; Cell cycle; Cell growth; Cell Transformation, Neoplastic; Deoxyribonucleic acid; Development and progression; DNA; Engineering and Technology; Epithelium; Fibroblasts; Gene expression; Genetic aspects; Genomes; Health aspects; Hyperplasia; Hyperplasia - pathology; Hypotheses; Inactivation; Medicine and Health Sciences; Merkel cell carcinoma; Merkel cell polyomavirus - genetics; Merkel Cells - metabolism; Merkel Cells - pathology; Mice; Mutation; Phenotypes; Polyomavirus Infections; Protein binding; Proteins; Research and Analysis Methods; Retina; Retinoblastoma; Rodents; Skin cancer; Skin Neoplasms - pathology; Transgenic animals; Transgenic mice; Tumor antigens; Tumor suppressor genes; Tumor Virus Infections; Tumorigenesis; Tumors; Viruses; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010551

Clear evidence supports a causal link between Merkel cell polyomavirus (MCPyV) and the highly aggressive human skin cancer called Merkel cell carcinoma (MCC). Integration of viral DNA into the human genome facilitates continued expression of the MCPyV small tumor (ST) and large tumor (LT) antigens in virus-positive MCCs. In MCC tumors, MCPyV LT is truncated in a manner that renders the virus unable to replicate yet preserves the LXCXE motif that facilitates its binding to and inactivation of the retinoblastoma tumor suppressor protein (pRb). We previously developed a MCPyV transgenic mouse model in which MCC tumor-derived ST and truncated LT expression were targeted to the stratified epithelium of the skin, causing epithelial hyperplasia, increased proliferation, and spontaneous tumorigenesis. We sought to determine if any of these phenotypes required the association between the truncated MCPyV LT and pRb. Mice were generated in which K14-driven MCPyV ST/LT were expressed in the context of a homozygous RbΔLXCXE knock-in allele that attenuates LT-pRb interactions through LT's LXCXE motif. We found that many of the phenotypes including tumorigenesis that develop in the K14-driven MCPyV transgenic mice were dependent upon LT's LXCXE-dependent interaction with pRb. These findings highlight the importance of the MCPyV LT-pRb interaction in an in vivo model for MCPyV-induced tumorigenesis.