Molecular characterization of the tumor/metastasis suppressor activity of plakoglobin

  • Author / Creator
    Aktary, Zackie M
  • Plakoglobin (γ-catenin) is a member of the Armadillo family of proteins and a homolog of β-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins and their signaling function by association with various intracellular proteins, from signaling molecules to transcription factors. However, while β-catenin has well-documented oncogenic potential, plakoglobin signaling capabilities are typically associated with tumor/metastasis suppression through mechanisms that have remained unclear. The focus of this thesis was to elucidate the molecular mechanisms by which plakoglobin regulates tumorigenesis and metastasis. To this end, we expressed plakoglobin in plakoglobin-null human carcinoma cells and compared the mRNA and protein profiles of plakoglobin expressing cells with those of parental cells. We identified a number of oncogenes and tumor/metastasis suppressors whose mRNA/protein levels were decreased and increased, respectively, upon plakoglobin expression. Extensive characterization of the plakoglobin expressing cells showed that plakoglobin regulates tumorigenesis and metastasis by interacting with and altering the levels, localization and/or function of growth/metastasis regulating proteins and/or by associating with transcription factors that regulate the expression of genes involved in these processes. Plakoglobin interacted with and increased both the protein and mRNA levels of the metastasis suppressor Nm23-H1 while only increasing the protein levels of Nm23-H2. Furthermore, in plakoglobin expressing cells, Nm23-H1/H2 complex was redistributed from the cytoplasm to the adherens junction at the membrane. We also showed that plakoglobin interacted with p53 and together they regulated the expression of a number of p53-target genes, including tumor suppressors SFN and NME1 and the tumor promoter SATB1. Concurrent with these changes, there was a significant decrease in cell proliferation and in vitro migration and invasion of plakoglobin expressing cells. These results clearly demonstrate that plakoglobin plays an active role in suppressing tumorigenesis/metastasis through both the regulation of gene expression and by interacting with and altering the levels, localization and function of various intracellular proteins involved in these processes. The larger implication of this work is that plakoglobin may be a useful marker for diagnosis and prognosis as well as a therapeutic target for the treatment of various cancers.

  • Subjects / Keywords
  • Graduation date
    Fall 2013
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Larue, Lionel (External; Institut Curie)
    • Jahroudi, Nadia (Medicine)
    • Mackey, John (Oncology)
    • Leng, Roger (Laboratory Medicine and Patholody)
    • Simmonds, Andrew (Cell Biology)