Activation of c-Myc and Cyclin D1 by JCV T-Antigen and beta -Catenin in Colon Cancer: e106257

• Published in: PloS one Vol. 9; no. 9
• Main Authors: Ripple, Michael J, Struckhoff, Amanda Parker, Trillo-Tinoco, Jimena, Li, Li, Margolin, David A, McGoey, Robin, Valle, Luis Del
• Format: Journal Article
• Language: English
• Published: 01-09-2014
• Subjects: JC virus
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0106257

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 beta -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 beta -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 beta -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 beta -catenin resulted in the significant enhancement of TCF-dependent promoter activity and activation of the beta -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.