This renewal supports investigation into the newest human cancer virus causing most Merkel cell carcinoma (MCC). We found Merkel cell polyomavirus (MCV or MCPyV) in 2008 by digital transcriptome subtraction as a clonally integrated infection of MCC. It is the seventh human cancer virus and the second discovered by our group (in addition to Kaposi's sarcoma Herpes virus, KSHV or HHV8). Our initial grant was highly successful, with over 35 studies published on MCV mRNA and protein expression patterns, MCV replication, cellular partners to MCV proteins, viral oncoprotein knockdown and diagnostic assays to determine MCV infection. Taken together, these studies show that MCV is the infectious cause for most MCC. These findings also led directly to new methods to diagnose and treat MCC (ECOG clinical trial 2612). In just five years, this research has radically improved prospects for diagnosis and treatment of this intractable cancer. As a new cancer virus, MCV can be exploited to uncover new etiologic cancer pathways. We find that an MCV oncoprotein, small T (sT) antigen, targets cellular protein regulation to activate both viral and cellular oncoproteins. It is a new viral reagent that now can be used to investigate how epigenetic protein translation contributes to cancer cell proliferation.
The aims of our renewal are: 1) to identify and characterize phosphodegron regulation of MCV large T (LT) and cellular oncoproteins, 2) to understand how MCV inactivates 4E-BP1, leading to dysregulated cap-dependent translation and cell transformation, 3) to identify the cellular oncogenic pathways that are activated by MCV and 4) to examine a transgenic mouse model for MCV-induced tumorigenesis. This proposal characterizes novel molecular mechanisms used by MCV to drive cancer cell proliferation and then applies these findings at the organismal level. These investigations will shed light on epigenetic cancer cell signaling and may speed development and testing of new cancer therapies.

Public Health Relevance

This proposal seeks to renew support for a very successful cancer research program. We recently discovered a new human virus, called Merkel cell polyomavirus (MCV), that causes most Merkel cell carcinomas, a severe skin cancer that is difficult to diagnose and having no specific treatment. Discovery of MCV has dramatically changed the prospects for this cancer, leading to new diagnostic tests and therapeutic trials. Our proposal seeks to understand how this virus causes cancer cell proliferation by examining one of the key viral proteins called small T antigen. Small T antigen is unique in that it changes cellular machinery to preserve both cellular and viral cancer-causing proteins. It also modifies the infected cell to produce new proteins that allow cancer cell division and proliferation. Understanding this mechanism will lead to improved methods to treat Merkel cell carcinomas and other cancers. In this proposal, we seek to understand how small T antigen disrupts controls on cancer protein synthesis and turnover, to find out which cellular proteins are activated in this process and to develop a mouse model that can be used in cancer drug screening.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA136806-06
Application #
8694310
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2009-03-13
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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:
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
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
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
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; 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
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
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
Kwun, Hyun Jin; Toptan, Tuna; Ramos da Silva, Suzane et al. (2014) Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding. Proc Natl Acad Sci U S A 111:E4342-9

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