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Permanent link (DOI): https://doi.org/10.7939/R38H5D

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Molecular characterization of the tumor/metastasis suppressor activity of plakoglobin Open Access

Descriptions

Other title
Subject/Keyword
Nm23
plakoglobin
14-3-3
SATB1
p53
cancer
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Aktary, Zackie M
Supervisor and department
Pasdar, Manijeh (Oncology)
Examining committee member and department
Mackey, John (Oncology)
Jahroudi, Nadia (Medicine)
Larue, Lionel (External; Institut Curie)
Simmonds, Andrew (Cell Biology)
Leng, Roger (Laboratory Medicine and Patholody)
Department
Department of Cell Biology
Specialization

Date accepted
2013-09-20T13:22:56Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R38H5D
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Aktary Z, Chapman K, Lam L, Lo A, Ji C, Graham K et al (2010). Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1. Oncogene 29: 2118-2129.Aktary Z, Pasdar M (2012). Plakoglobin: role in tumorigenesis and metastasis. International journal of cell biology 2012: 189521.Aktary Z, Kulak S, Mackey J, Jahroudi N, Pasdar M (2013). Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3sigma. Journal of cell science.Aktary Z, Pasdar M. Plakoglobin downregulates the expression of SATB1 and suppresses in vitro proliferation, migration and invasion. Revised and submitted for PLoS One.

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