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Title page for ETD etd-06232008-105114


Type of Document Dissertation
Author Lund, Sabata Silva Constancio
Author's Email Address sabata.s.constancio@vanderbilt.edu
URN etd-06232008-105114
Title Studies on Src tyrosine kinase in tumorigenic cell growth and invasion
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Robert J. Coffey, M.D. Committee Chair
Ambra Pozzi, Ph.D. Committee Member
Matthew J. Tyska, Ph.D. Committee Member
Stephen R. Hann, Ph.D. Committee Member
Steven K. Hanks, Ph.D. Committee Member
Keywords
  • b-catenin
  • invasion
  • APC
  • soft-agar
  • Src kinase
Date of Defense 2008-06-16
Availability unrestricted
Abstract
This project aims to better understand the role of Src kinase on the development of colon cancer. Enhanced Src expression and activity are commonly elevated in colon cancer, with progressively higher activity observed as tumors progress and metastasize, however, the specific mechanism by which Src promotes cancer progression are still under investigation. First, we examined the potential for biological cooperativity between APC (adenomatous polyposis coli), a tumor suppressor often mutated in early stages of colon cancer, and elevated Src activity, using conditionally immortalized mouse colon epithelial cell lines, IMCE (APC +/min) and YAMC (APC +/+) as a model. The APC genotype did not affect the ability of Src to disrupt cell-cell junctions and promote cell invasiveness. However, IMCE cells exhibited increased capacity for oncogenic Src-mediated anchorage-independent proliferation as compared to YAMC cells. This property was correlated with enhanced -catenin expression and activity, but not with enhanced ERK phosphorylation. The selective Src inhibitor, AZD0530, was found to be effective in blocking both cell invasion and proliferation. Second, we investigated the possible role for one of the major Src substrates, CAS (Crk associated substrate) in epithelial cell polarization. Stable depletion of CAS did not affect proliferation on the colon epithelial cell lines Caco2 and HCA7, however it increased thee transepithelial cell resistance of Caco2 cells compared to control cells. Furthermore, fluorescently tagged CAS was shown to localize to cell-cell adhesions in polarized Caco2 cells.
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