We have recently discovered a new human polyomavirus monoclonally-integrated into human Merkel cell carcinomas (MCC) that we call Merkel cell polyomavirus (MCPyV). MCC is a rare neuroectodermal cancer suspected to be caused by a viral infection because of its unusual epidemiology. It is the most aggressive skin cancer and only 50% of patients with advanced disease survive 9 months or longer. MCPyV has a 5.4 kbase genome closely related to murine and African green monkey lymphotropic polyomaviruses (MuPyV and LPyV, respectively). MCPyV is distantly related to SV40 and the four known human polyomaviruses. Human serosurveys show that 15-30% of populations from the US, Japan and Germany have cross-reactive antibodies to LPV which may actually represent reactivity to MCPyV infection. We find similar MCPyV infection rates using direct detection of MCPyV genome from peripheral blood cells. If confirmed, these findings suggest that over a billion persons have been exposed to MCPyV infections worldwide. Southern blotting shows that MCPyV is integrated into MCC genome at different sites in a somatic and monoclonal pattern. One cellular integration site has been defined as the receptor-type protein tyrosine phosphatase-gamma (PTPRG) intron 1. MCPyV also expresses a highly conserved T antigen in tumors. The N-terminus of MCPyV encodes transformation-associated DnaJ and LXCXE pocket protein-binding domains. All tumor- derived MCPyV T antigens, however, possess T antigen mutations that eliminate T antigen origin binding and/or plasmid replication functions. These functions are not needed to maintain integrated virus, suggesting that MCC arises in at least two steps: first, MCPyV integrates into the host genome;second, truncation mutations arise allowing expression of N-terminal transforming domains, but eliminating deleterious C- terminal domains. MCPyV may play a role in tumorigenesis through insertional mutagenesis, expression of T antigen or both. Our proposal seeks to understand these mechanisms for transformation and oncogenesis by 1) identifying additional cell integration sites, 2) analyzing T antigen transforming functions in rodent cells and in cell signaling assays, 3) performing cell-wide proteomic analysis following T antigen expression, 4) identifying novel cellular T antigen direct interactors and 5) generating transgenic mice with MCPyV T antigen expression targeted to Merkel mechanoreceptor cells. Through this systematic approach we anticipate we will learn how this new virus contributes to human carcinogenesis.
This proposal seeks to understand how Merkel cell virus (MCV) contributes to human cancers. MCV has been found as an integrated virus in Merkel cell carcinoma where it expresses T antigen, an oncoprotein that has been well-characterized from closely-related viruses. This proposal will investigate similarities and differences between MCV T antigen and T antigen from other viruses as well as dysregulation of cellular proteins from MCV integration and T antigen expression. Finally, we seek to generate a model system for MCV tumorigenesis that will be useful for drug screening and prevention.
|Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro et al. (2016) Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. Proc Natl Acad Sci U S A 113:8466-71|
|Toptan, Tuna; Yousem, Samuel A; Ho, Jonhan et al. (2016) Survey for human polyomaviruses in cancer. JCI Insight 1:|
|Dulmage, B O; Feng, H; Mirvish, E et al. (2015) Black cat in a dark room: the absence of a directly oncogenic virus does not eliminate the role of an infectious agent in cutaneous T-cell lymphoma pathogenesis. Br J Dermatol 172:1449-51|
|Shuda, Masahiro; Guastafierro, Anna; Geng, Xuehui et al. (2015) Merkel Cell Polyomavirus Small T Antigen Induces Cancer and Embryonic Merkel Cell Proliferation in a Transgenic Mouse Model. PLoS One 10:e0142329|
|Richards, Kathleen F; Guastafierro, Anna; Shuda, Masahiro et al. (2015) Merkel cell polyomavirus T antigens promote cell proliferation and inflammatory cytokine gene expression. J Gen Virol 96:3532-44|
|Ho, Jonhan; Jedrych, Jaroslaw J; Feng, Huichen et al. (2015) Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients. J Infect Dis 211:1560-5|
|Kwun, Hyun Jin; Shuda, Masahiro; Camacho, Carlos J et al. (2015) Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen. J Virol 89:4191-200|
|Wendzicki, Justin A; Moore, Patrick S; Chang, Yuan (2015) Large T and small T antigens of Merkel cell polyomavirus. Curr Opin Virol 11:38-43|
|Shuda, Masahiro; Velásquez, Celestino; Cheng, Erdong et al. (2015) CDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation. Proc Natl Acad Sci U S A 112:5875-82|
|Chang, Yuan; Moore, Patrick (2014) Twenty years of KSHV. Viruses 6:4258-64|
Showing the most recent 10 out of 25 publications