Date of Graduation
12-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Joya Chandra, Ph.D.
Committee Member
Gary Gallick, Ph.D.
Committee Member
Candelaria Gomez-Manzano, M.D.
Committee Member
Juan Fueyo, M.D.
Committee Member
Zahid Siddik, Ph.D.
Abstract
Src family kinases (SFKs) are commonly over-expressed and/or activated in glioblastoma multiforme (GBM), where they serve as key mediators of GBM cell proliferation, survival, invasion and angiogenesis. Mechanisms of allosteric SFK activation are well described; however, the SFK Fyn is commonly up-regulated at the mRNA level in multiple human cancers, including GBM, where the mode of increased expression is poorly understood. Since activating mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in GBM, we examined whether EGFR could induce Fyn expression. Here, we found that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants, EGFRΔIII and R108K, induce a substantial up-regulation of Fyn expression. Furthermore, it was determined that Fyn expression is up-regulated across a panel of patient-derived GBM stem cells (GSCs) relative to normal progenitor controls. Inhibition of Fyn proved to be biologically relevant, as Fyn depletion significantly (pp
Keywords
EGFR; Glioblastoma; SRC