title: Activation of c-Myc and Cyclin D1 by JCV T-Antigen and β-catenin in colon cancer.
abstract: During the last decade, mounting evidence has implicated the human neurotropic virus JC virus in the pathology of colon cancer. However, the mechanisms of JC virus-mediated oncogenesis are still not fully determined. One candidate to mediate these effects is the viral early transcriptional product T-Antigen, which has the ability to inactivate cell cycle regulatory proteins such as p53. In medulloblastomas, T-Antigen has been shown to bind the Wnt signaling pathway protein β-catenin; however, the effects of this interaction on downstream cell cycle regulatory proteins remain unknown. In light of these observations, we investigated the association of T-Antigen and nuclear β-catenin in colon cancer cases and the effects of this complex in the activation of the transcription and cell cycle regulators c-Myc and Cyclin D1 in vitro. Gene amplification demonstrated the presence of viral sequences in 82.4% of cases and we detected expression of T-Antigen in 64.6% of cases by immunohistochemistry. Further, we found that T-Antigen and β-catenin co-localized in the nuclei of tumor cells and we confirmed the physical binding between these two proteins in vitro. The nuclear presence of T-Antigen and β-catenin resulted in the significant enhancement of TCF-dependent promoter activity and activation of the β-catenin downstream targets, c-Myc and Cyclin D1. These observations provide further evidence for a role of JCV T-Antigen in the dysregulation of the Wnt signaling pathway and in the pathogenesis of colon cancer.
authors.affiliation: Stanley S. Scott Cancer Center, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America; Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ripple
authors.affiliation: Stanley S. Scott Cancer Center, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Parker Struckhoff
authors.affiliation: Stanley S. Scott Cancer Center, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Jimena
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.affiliation: Institute for Translational Research, Ochsner Clinic Foundation, New Orleans, Louisiana, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Colorectal Surgery, Ochsner Clinic Foundation, New Orleans, Louisiana, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Margolin
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: McGoey
authors.affiliation: Stanley S. Scott Cancer Center, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America; Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
mesh_terms: D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D066298:In Vitro Techniques; D007577:JC Virus / Q000276:immunology* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000957:Antigens, Viral, Tumor; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D019938:Cyclin D1