Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice.
In recent years, there has been mounting evidence pointing to the association of polyomaviruses with a wide range of human cancers. The human neurotropic polyomavirus, JCV, infecting greater than 75% of the human population produces a regulatory protein named T-antigen which is expressed at the early phase of viral lytic infection and plays a critical role in completion of the viral life cycle. Furthermore, this protein has the ability to transform neural cells in vitro and its expression has been detected in several human neural-origin tumors. To further investigate the oncogenic potential of the JCV early protein in vivo, transgenic mice expressing JCV T-antigen under the control of its own promoter were generated. Nearly 50% of the animals developed large, solid masses within the base of the skull by 1 year of age. Evaluation of the location as well as histological and immunohistochemical data suggest that the tumors arise from the pituitary gland. As T-antigen is known to interact with several cell cycle regulators, the neoplasms were analysed for the presence of the tumor suppressor protein, p53. Immunoprecipitation/Western blot analysis demonstrated overexpression of wild-type, but not mutant p53 within tumor tissue. In addition, co-immunoprecipitation established an interaction between p53 and T-antigen and overexpression of p53 downstream target protein, p21/WAF1. This report describes the analysis of inheritable pituitary adenomas induced by expression of the human polyomavirus, JCV T-antigen in transgenic mice where T-antigen disrupts the p53 pathway by binding to and sequestering wild-type p53. This animal model may serve as a useful tool to further evaluate mechanisms of tumorigenesis by JCV T-antigen.
Gordon
J
J
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Del Valle
L
L
Otte
J
J
Khalili
K
K
D000236:Adenoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology / Q000821:virology*; D000818:Animals; D021461:Animals, Outbred Strains; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D002472:Cell Transformation, Viral / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015967:Gene Expression Regulation, Viral; D016158:Genes, p53; D016679:Genome, Viral; D007414:Intestinal Neoplasms / Q000235:genetics / Q000821:virology; D007577:JC Virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D010911:Pituitary Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology / Q000821:virology*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53