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Constitutive ß-Catenin Signaling by the Viral Chemokine Receptor US28

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
7
Issue
11
Identifiers
DOI: 10.1371/journal.pone.0048935
Keywords
  • Research Article
  • Biology
  • Biochemistry
  • Drug Discovery
  • Model Organisms
  • Animal Models
  • Mouse
  • Molecular Cell Biology
  • Signal Transduction
  • Signaling Cascades
  • Wnt Signaling Cascade
  • Signaling In Cellular Processes
  • Beta-Catenin Signaling
  • Chemistry
  • Medicinal Chemistry
  • Medicine
  • Oncology
  • Basic Cancer Research
Disciplines
  • Medicine

Abstract

Chronic activation of Wnt/ß-catenin signaling is found in a variety of human malignancies including melanoma, colorectal and hepatocellular carcinomas. Interestingly, expression of the HCMV-encoded chemokine receptor US28 in intestinal epithelial cells promotes intestinal neoplasia in transgenic mice, which is associated with increased nuclear accumulation of ß-catenin. In this study we show that this viral receptor constitutively activates ß-catenin and enhances ß-catenin-dependent transcription. Our data illustrate that this viral receptor does not activate ß-catenin via the classical Wnt/Frizzled signaling pathway. Analysis of US28 mediated signaling indicates the involvement of the Rho-Rho kinase (ROCK) pathway in the activation of ß-catenin. Moreover, cells infected with HCMV show significant increases in ß-catenin stabilization and signaling, which is mediated to a large extent by expression of US28. The modulation of the ß-catenin signal transduction pathway by a viral chemokine receptor provides alternative regulation of this pathway, with potential relevance for the development of colon cancer and virus-associated diseases.

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