title: Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities.
abstract: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Cheng
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Paulson
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D006133:Growth Substances / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D059965:Merkel cell polyomavirus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D006133:Growth Substances